Pyrimidinone compounds and pharmaceutical compositions containing them

ABSTRACT

A group of novel pyrimidone compounds are inhibitors of the enzyme LDL PLA 2  and therefore of use in treating atherosclerosis.

The present invention relates to certain novel pyrimidinone compounds,processes for their preparation, intermediates useful in theirpreparation, pharmaceutical compositions containing them and their usein therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2enzyme Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂), the sequence.isolation and purification thereof, isolated nucleic acids encoding theenzyme, and recombinant host cells transformed with DNA encoding theenzyme. Suggested therapeutic uses for inhibitors of the enzyme includedatherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardialinfarction, reperfusion injury and acute and chronic inflammation. Asubsequent publication from the same group further describes this enzyme(Tew D et al, Arterioscler Thromb Vas Biol 1996:16:591-9) wherein it isreferred to as LDL-PLA₂. A later patent application (WO 95/09921, IcosCorporation) and a related publication in Nature (Tjoelker et al, vol374, Apr. 6, 1995, 549) describe the enzyme PAF-AH which has essentiallythe same sequence as Lp-PLA₂ and suggest that it may have potential as atherapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA₂ is responsible for the conversion ofphosphatidylcholine to lysophosphatidylcholine, during the conversion oflow density lipoprotein (LDL) to its oxidised form. The enzyme is knownto hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine, a component of oxidised LDL, known to be apotent chemoattractant for circulating monocytes. As such,lysophosphatidylcholine is thought play a significant role inatherosclerosis by being responsible for the accumulation of cellsloaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA₂enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. AnLp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In addition, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂. Examples ofsuch disorders include psoriasis.

Furthermore, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves lipid peroxidation in conjunction withLp-PLA₂ activity to produce the two injurious products,lysophosphatidylcholine and oxidatively modified fatty acids. Suchconditions include the aforementioned conditions atherosclerosis,diabetes, rheumatoid arthritis, stroke, myocardial infarction,reperfusion injury and acute and chronic inflammation. Further suchconditions include various neuropsychiatric disorders such asschizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).

Patent applications WO 96/12963, WO 96/13484, WO 96119451, WO 97/02242,WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKlineBeecham plc) disclose inter alia various series of4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitorsof the enzyme Lp-PLA₂. These are irreversible, acylating inhibitors (Tewet al, Biochemistry, 37, 10087, 1998). GB 1 582 527 describes, ascompounds of formula (7), a group of pyrimidone compounds of the formula(A):

in which Alk is lower alkyl, Het is selected from 2- or 4-imidazolyl,2-pyridyl, 2-thiazolyl, 3-isothiazolyl, 1,2,5-thiadiazolyl and n is from1 to 4. These compounds are said to be useful as intermediates in thepreparation of further compounds which are H2 antagonists.

A new class of pyrimidone compounds has now been identified which areinhibitors of the enzyme Lp-PLA₂.

Accordingly, the present invention provides compounds of formula (I):

in which:

Z is a bond and R¹ is halogen; or

Z is CR³R⁴, where R³ and R⁴ are each hydrogen or C₍₁₋₄₎alkyl, or R³ andR⁴ together with the intervening carbon atom form a C₍₃₋₆₎cycloalkylring; and

R¹ is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or4 substituents selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, oxo, hydroxy, halogen, CN, COR⁵,COOR⁵, CONR₅R⁶, NR⁵COR⁶, SO₂NR⁵R⁶, NR⁵SO₂R⁶, NR⁵R⁶, mono toperfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;

X is O or S;

Y is a group of formula —A¹—A²−A³— in which A¹ and A³ each represent abond or a straight chain or branched C₍₁₋₁₀₎alkylene group and A²represents a bond or O, S, SO, SO₂, CO, C═CH₂, CH═CH , C≡C, CONH, NHCO,or CR⁵R⁶, providing that when A² is O, S, SO, SO₂ or CONH, A³ containsat least two carbon atoms linking the A² group and the CH₂ group informula (I);

R² is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or4 substituents selected from the substituents hereinbefore defined forR¹, as well as aryl and arylC₍₁₋₄₎alkyl,

W is a bond and R⁷ is hydrogen; or

W is SO₂ or a bond; and

R⁷ is R¹ or a hydrocarbyl group which hydrocarbyl group may beoptionally interupted within the carbon chain by a group selected fromO, COO, OCO, CO, CONR⁸, NR⁸CO, NR⁸CONR⁹, NR⁸COO, OCONR⁸, and NR⁸, andwhich hydrocarbyl group may also be optionally substituted by 1 or 2substituents selected from mono to perfluoro-C₍₁₋₄₎alkyl, OR⁸, COOR⁸,CONR⁸R⁹, NR⁸COR⁹, NR⁸CONR⁹R¹⁰, NR⁸COOR⁹, OCONR⁸R⁹, NR₁₁R¹² and R¹;

R⁵ and R⁶ are independently hydrogen or C₍₁₋₂₀₎alkyl, for instanceC₍₁₋₄₎alkyl (e.g. methyl or ethyl);

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, C₍₁₋₂₀₎alkyl(for instance C₍₁₋₁₅₎alkyl), (which may optionally be fluorinated,including up to perfluorinated on the terminal 1 to 3 carbon atoms),C₍₁₋₂₀₎alkenyl (preferably C₍₁₂₋₁₈₎alkenyl), aryl, arylC₍₁₋₁₀₎alkyl,C₍₁₋₁₀₎alkoxyC₍₁₋₁₀₎alkyl, or aryloxyC₍₁₋₁₀₎alkyl and in which an arylgroup may have one or two substituents selected from halogen,C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎alkoxy, aryloxy and COOC₍₁₋₂₀₎alkyl; and

R¹¹ and R¹² are independently selected from one of the valueshereinbefore defined for R⁸ and R⁹ or R¹¹ and R¹² together with thenitrogen atom to which they are attached form a 5- to 7 membered ringoptionally containing one or two further heteroatoms selected fromoxygen, nitrogen and sulphur, and optionally substituted by one or twosubstituents selected from hydroxy, oxo, C₍₁₋₄₎alkyl, phenyl, or benzyl.

Preferably, Z is CH₂.

Representative examples of R¹ when an aryl group include phenyl andnaphthyl. Representative examples of R¹ when a heteroaryl group includepyridyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, quinolyl,benzothiazolyl, pyridazolyl and pyrazinyl.

Preferably R¹ is a 5- or 6-membered, monocyclic heteroaryl groupcontaining 1 or 2 nitrogen heteroatoms, preferably pyridyl, pyrimidyl orpyrazolyl, more preferably, pyrid-4-yl or pyrimid-5-yl and optionallysubstituted by 1 or 2 substituents preferably selected fromarylC₍₁₋₄₎alkyl (e.g. benzyl), C₍₁₋₈₎alkyl (e.g. methyl or ethyl),halogen (e.g. chlorine), oxo, hydroxy, C₍₁₋₄₎alkoxy (e.g. methoxy) andarylC₍₁₋₄₎alkoxy (e.g. benzyloxy). More preferably, R¹ is pyrimid-5-ylor a 2-oxo-pyrimid-5-yl group, optionally substituted at N-1 byC₍₁₋₈₎alkyl (e.g. undecyl, methyl or ethyl), or a 2-C₍₁₋₄₎alkoxy- orarylC₍₁₋₄₎alkoxy-pyrimid-5-yl group.

Preferably, ZR¹ is 2-oxo-pyrid-4-ylmethyl, pyrimid-5-ylmethyl or2-oxo-pyrimid-5-ylmethyl in which the 2-oxo-pyrimid-5-yl moiety is ashereinbefore defined.

Preferably X is S.

Preferred compounds of formula (I) include those in which Y is a bond,i.e. A¹, A² and A³ each represent a bond. Other preferred examples ofthe groups A¹ and A³ are straight chain C₍₁₋₁₀₎alkylene groups. When A²is other than a bond, A¹ is preferably a bond. Preferred examples of A²when other than a bond include CO, C═CH₂ and O, the CO group beingespecially preferred. Other preferred examples of Y are (CH₂)₇ andCO(CH₂)₆.

Representative examples of R² when an aryl group include phenyl andnaphthyl. Representative examples of R² when a heteroaryl group includepyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl,quinolyl,benzothiazolyl, pyridazolyl and pyrazinyl Preferably, R² isphenyl optionally substituted by 1, 2 or 3 substituents selected fromhalogen (e.g. chlorine or fluorine), C₍₁₋₄₎alkyl (e.g. methyl or ethyl)or C₍₁₋₄₎alkoxy (e.g. methoxy). Further optional substituents includephenyl and benzyl.

Representative examples of R²YCH₂X include 4-fluorobenzylthiogroup,4-chlorophenylheptylthio and 4-chlorophenyl-1-oxaheptylthio. Preferably,R²YCH₂X is 4-fluorobenzylthio group.

Preferably W is a bond.

Representative examples of R⁷ when a hydrocarbyl group includeC₍₁₋₂₀₎alkyl, C₍₂₋₂₀₎alkenyl, C₍₂₋₂₀₎alkynyl, C₍₃₋₆₎cycloalkyl,C₍₃₋₆₎cycloalkylC₍₁₋₅₎alkyl, or C₍₁₋₁₅₎alkoxyC₍₁₋₁₀₎alkyl each of whichmay be optionally substituted by 1 or 2 substituents as hereinbeforedefined.

Preferably, W is a bond and R⁷ is C₍₁₋₂₀₎alkyl, especiallyC₍₁₀₋₂₀₎alkyl. Preferably, R⁷ is also C₍₁₋₁₀₎alkyl, more preferably aC₍₁₋₆₎alkyl which is substituted by one or two substituents selectedfrom hydroxy, C₍₁₋₁₀₎alkoxy (e.g. methoxy), COOC₍₁₋₁₀₎alkyl (e.g.COOCH₃, COOC₂H₅), CONR⁸R⁹, NR⁸CONR⁹R¹⁰, NHCOR⁸ (in which R⁸, R^(9 and R)¹⁰ is each independently C₍₁₋₂₀₎alkyl e.g. methyl). Further optionalsubstituents include aryl, preferably phenyl which may be optionallysubstituted by COOC₍₁₋₆₎alkyl (e.g methyl) and heteroaryl (for instancepyridyl, imidazolyl, furanyl, thienyl and 2-oxo pyrrolidinyl). Preferredexamples of the substituent NR¹¹R¹² include morpholino, piperidino or2-oxo-pyrrolidino group.

A preferred sub-group of compounds of formula (I) are those in which Wis a bond and R⁷ is a phenyl or a phenylC₍₁₋₈₎alkyl group, for instancebenzyl or phenethyl, substituted in the phenyl ring by 1 or 2substituents selected from C₍₆₋₁₂₎alkyl (for instance hexyl and decyl),C₍₆₋₁₂₎alkoxy, COOH, COOC₍₆₋₁₂₎alkyl and CONHC₍₆₋₁₂₎alkyl.Alternatively, R⁷ maybe heteroarylC₍₁₋₈₎alkyl, preferablyheteroarylC₍₁₋₃₎alkyl in which the heteroaryl ring is monocyclic with 5to 6 members and one or two heteroatoms selected from nitrogen, oxygenand sulphur, such as pyridyl, furanyl, thienyl and imidazolyl. A furtherpreferred subgroup of compounds of formula (I) are those in which W is abond and R⁷ is a group of the formula (CH₂)_(n)BR¹³ where n is aninteger from 1 to 6, preferably 1 to 4, B is selected from NR¹⁴CO,CONR¹⁴, NR¹⁴CONR¹⁵, NR¹⁵COO (in which R¹⁴ and R¹⁵ are independentlyselected from hydrogen or C₍₁₋₆₎alkyl, preferably hydrogen) and R¹³ isC₍₈₋₁₈₎alkyl (which may optionally be fluorinated, including up toperfluorinated on the terminal 1 to 3 carbon atoms), C₍₈₋₁₈₎alkenyl,phenyl C₍₁₋₆₎alkyl and phenylC₍₁₋₈₎alkoxyC₍₁₋₆₎alkyl in which phenyl maybe optionally substituted by halogen or C₍₁₋₆₎alkyl. Prefered examplesof C₍₈₋₁₈₎alkyl are straight chains and include octyl, dodecyl and fattyalkyl groups such as lauryl and stearyl. Preferred values ofC₍₈₋₁₈₎alkenyl include octadec-9-(Z)-en-1yl. Preferred examples ofoptionally substituted phenylC₍₁₋₆₎alkyl andphenylC₍₁₋₈₎alkoxyC₍₁₋₆₎alkyl include 4-fluorophenylhexyl,4-pentylphenylethyl and 4-fluorophenylhexoxyethyl. Particularlypreferred compounds of formula (I) are those in which R¹² isC₍₁₂₋₁₈₎alkyl or C₍₁₂₋₁₈₎alkenyl. Such a long, lipophilic substituent isfound to be especially beneficial for enzyme inhibition

When used herein, the term ‘alkyl’ and similar terms such as ‘alkoxy’includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “hydrocarbyl” refers to a group having from 1to 20 carbon atoms which may be in a straight chain or a branched chainand include a saturated carbocyclic ring having from 3 to 6 carbon atomsand which chain may contain unsaturation (double and/or triplecarbon-carbon bonds).

When used herein, the term ‘aryl’ refers to, unless otherwise defined, amono- or bicyclic aromatic ring system containing up to 10 carbon atomsin the ring system, for instance phenyl or naphthyl.

When used herein, the term ‘heteroaryl’ refers to a mono- or bicyclicheteroaromatic ring system comprising up to four, preferably 1 or 2,heteroatoms each selected from oxygen, nitrogen and sulphur. Each ringmay have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclicheteroaromatic ring system may include a carbocyclic ring.Representative examples include pyridyl, pyridyl N-oxide, pyrimidyl,pyrazolyl, furyl, thienyl, thiazolyl, pyridazolyl and pyrazinyl,quinolyl and benzothiazolyl.

When used herein, the terms ‘halogen’ and ‘halo’ include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively. Compounds of formula (I) are inhibitors of Lp-PLA₂ and assuch are expected to be of use in treating atherosclerosis and the otherdisease conditions noted elsewhere. Such compounds are found to act asinhibitors of Lp-PLA₂ in in vitro assays

Particularly preferred compounds of formula (I) are

2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one;

1-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;

1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;

1-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;and

1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are recrystallised from organic solvents, solvent of crystallisationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or recrystallised from solvents containingwater. In such cases water of hydration may be formed. This inventionincludes within its scope stoichiometric hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂₎and as such areexpected to be of use in therapy, in particular in the treatment ofatherosclerosis. In a further aspect therefore the present inventionprovides a compound of formula (I) for use in therapy. The compounds offormula (I) are inhibitors of lysophosphatidylcholine production byLp-PLA₂ and may therefore also have a general application in anydisorder that involves endothelial dysfunction, for exampleatherosclerosis, diabetes, hypertension, angina pectoris and afterischaemia and reperfusion. In addition, compounds of formula (I) mayhave a general application in any disorder that involves lipidperoxidation in conjunction with enzyme activity, for example inaddition to conditions such as atherosclerosis and diabetes, otherconditions such as rheumatoid arthritis, stroke, inflammatory conditionsof the brain such as Alzheimer's Disease, myocardial infarction,reperfusion injury, sepsis, and acute and chronic inflammation. Furthersuch conditions include various neuropsychiatric disorders such asschizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes: with the formation oflysophosphatidylcholine and oxidised free fatty acids: with lipidperoxidation in conjunction with Lp PLA2 activity; or with endothelialdysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with anti-hyperlipidaemicor anti-atherosclerotic or anti-diabetic or anti-anginal oranti-inflammatory or anti-hypertension agents. Examples of the aboveinclude cholesterol synthesis inhibitors such as statins, anti-oxidantssuch as probucol, insulin sensitisers, calcium channel antagonists, andanti-inflammatory drugs such as NSAIDs.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Suitable pharmaceutical compositions include thosewhich are adapted for oral or parenteral administration or as asuppository.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository. Compounds offormula (I) which are active when given orally can be formulated asliquids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges. A liquid formulation will generally consist of asuspension or solution of the compound or pharmaceutically acceptablesalt in a suitable liquid carrier(s) for example, ethanol, glycerine,non-aqueous solvent, for example polyethylene glycol, oils, or waterwith a suspending agent, preservative, flavouring or colouring agent. Acomposition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule. Typical parenteral compositionsconsist of a solution or suspension of the compound of formula (I) in asterile aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration. Atypical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule. Each dosage unit for oral administration contains preferablyfrom 1 to 500 mg (and for parenteral administration contains preferablyfrom 0.1 to 25 mg) of a compound of the formula (I). The daily dosageregimen for an adult patient may be, for example, an oral dose ofbetween 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or anintravenous, subcutaneous, or intramuscular dose of between 0.1 mg and100 mg, preferably between 0.1 mg and 25 mg, of the compound of theformula (I), the compound being administered 1 to 4 times per day.Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

Compounds of formula (I) may be conveniently prepared from readilyavailable starting materials by adapting synthetic methodology wellknown in the art for the preparation and derivatisation of pyrimidonesby a process.

Accordingly, in a first aspect, the present invention provides a processfor preparing a compound of formula (I) which process comprises:

(a) treating a compound of formula (IIA):

 which R¹ and Z are as hereinbefore defined; with a compound of formula(III):

R²YCH₂L¹  (III)

in which Y and R² are as hereinbefore defined and L¹ is a leaving groupe.g. bromine or iodine; to give a compound of formula (IA):

in which Z, Y, R¹ and R² are as hereinbefore defined and X is S; or

(b) treating a compound of formula (IV):

in which Z and R₁ are as hereinbefore defined and L² is a leaving,group, e.g. halogen such as chlorine or bromine, alkylthio such asmethylthio, or —NHNO₂, with a compound of formula (V):

R²YCH₂XH  (V)

in which X, Y and R² are as hereinbefore defined; advantageously at anelevated temperature, in a solvent such as pyridine, to give a compoundof formula (IA); and thereafter, and if so desired;

treating, a compound of formula (IA) form (a) or (b) above with acompound of formula (VI):

R⁷WL¹  (VI)

in which L¹, W and R⁷ are as hereinbefore defined; to give a compound offormula (IB):

in which X, Y, Z, R₁ and R² are as hereinbefore defined and WR⁷ is ashereinbefore defined, other than —H; or

(c) treating a compound of formula (IIB):

in which W is a bond, Z and R¹ are as hereinbefore defined and R⁷ are ashereinbefore defined, other then H,

with a compound of formula (III) as hereinbefore defined, to obtain acompound of formula (IB); and, thereafter and if so desired;

treating a compound of formula (IA) or (IB) in which X is S with acompound of formula (V):

R²YCH₂OH  (VII)

in which Y and R² are as hereinbefore defined;

to give a corresponding compound of formula (I) in which X is O.

In the above process, the reaction of the compounds of formulae (IIA/B)and (III) is advantageously effected in the presence of a base such assodium ethoxide, potassium carbonate, preferably in a solvent such asethanol or dimethylformamide, or a base such as di-isopropyl ethylamine,preferably in a solvent such as dichloromethane.

In the above process, the reaction of the compounds of formulae (IA) and(VI) is advantageously effected at a temperature of 20-100 degrees C.,in the presence of sodium hydride in a solvent such asdimethylformamide; or by the compound of formula (IA) being pre-treatedwith tributyl tin chloride in the presence of di-isopropylethylamine,for example in a dichloromethane solvent at reflux temperature, followedby addition of (VI) Alternatively, the compound of formula (IA) may betreated directly with a compound of formula (VI) anddi-isopropylethylamine in a dichloromethane solvent at room temperature.

In the above processes, the reaction of the compounds of formulae(IA/IB) and (VII) is conveniently effected in the presence of pyridineat an elevated temperature, containing a catalytic amount of4-dimethylaminopyridine.

A compound of formula (I) in which Z is a bond and R¹ represents halogenmay be obtained by treating a compound of formula (VIII):

in which W, Y, R², and R⁷ are as hereinbefore defined; with ahalogenating agent, preferably with bromine to form a compound offormula (I) in which Z is a bond and R¹ is bromine, the reaction beingadvantageously effected in a solvent such as dichloromethane.

A compound of formula (IIA) may be obtained from a compound of formula(IX):

L³OCOCH₂ZR¹  (IX)

in which L³ is C₍₁₋₆₎alkyl, for instance methyl, and Z and R¹ are ashereinbefore defined;

by the initial treatment thereof with a formylating agent such ethylformate in the presence of a strong base such as potassium t-butoxide orsodium hydride, to give an enolate metal salt compound of formula (X):

in which L³, Z and R¹ are as hereinbefore defined and M is a metalcation, for instance sodium or potassium. Further treatment of acompound of formula (X) or a salt thereof with thiourea leads to acompound of formula (IIA). The two steps, starting form the compound offormula (IX) may conveniently be carried out as a “one-pot” process.

A compound of formula (IIB) may be obtained from a compound of formula(X), in a series of steps. In a first step, a compound of formula (X) isconverted into the corresponding methyl enol ether by treatment with amethylating agent such as dimethyl sulphate in the presence of a basesuch as potassium carbonate. The corresponding carboxylic acid may thenbe obtained by conventional hydrolysis, for instance basic hydrolysis,using, for instance aqueous sodium hydroxide. The acid may then beconverted into the corresponding acyl chloride, by treatment with oxalylchloride, and the acyl chloride treated with potassium thiocyanate in asolvent such as acetonitrile, to give an intermediate of the formula(XI):

in which R¹ and Z are as hereinbefore defined. Treatment of a compoundof formula (XI) with a compound of formula (XII):

R⁷WNH₂  (XII)

in which R⁷ is as hereinbefore defined and W is a bond, followed by theaddition of an organic base such as sodium ethoxide, leads to a compoundof formula (IIB).

A compound of formula (IV) in which L² is N(H)NO₂ can be convenientlyprepared by reacting a compound of formula (X) above with a compound offormula (XIII):

in which the reaction is carried out in a conventional manner.

A compound of formula (VIII) may be obtained by treating a3,3-dialkoxypropionic ester of the formula (XIV):

(L³)O₂CCH₂CH(OL³)₂  (XIV)

in which L³ is as hereinbefore defined;

with a thiourea of the formula (XV):

R⁷NHCSNH₂  (XV)

in which R⁷ is as hereinbefore defined;

in the presence of sodium hydride followed by aqueous acetic acid.

Compounds of formula (I) in which R⁷ comprises an amide moiety can beprepared from a precursor comprising an ester, for instance a methyl orethyl ester, by first converting the ester to an acid, by hydrolysis andthen treating the acid with an appropriate amine, under amide bondforming conditions. The acid may preferably be converted into anactivated derivative, prior to amide bond formation.

Compounds of formula (I) in which R⁷ comprises a urea moiety can beprepared from a precursor comprising an amine moiety, by treating theamine with an isocyanate, under urea forming conditions, well known inthe art.

The present invention will now be illustrated by the following examples.

Intermediate A1 8-Bromo-1-(4-chlorophenyl)octan-1-one

To a stirring suspension of aluminium chloride (33.6 g) in drydichloromethane (474 ml) was added 8-bromo-n-octanoyl chloride (67.8 g)over 10 min. Chlorobenzene (123 ml) was then added over 10 min and themixture allowed to stir at 25° C. for 74 h and stood for 64 h. Themixture was poured into ice/water (540 ml) and diethyl ether (1.3 L).The organic layer was removed and was washed with water (540 ml),saturated sodium hydrogen carbonate (540 ml), water (400 ml) and brine(400 ml) and dried over magnesium sulfate. Removal of the organic layerunder reduced pressure and chromatography of the residue on silica gelusing 5% ethyl acetate in hexane gave8-bromo-1-(4-chlorophenyl)octan-1-one (35.5 g). ¹H-NMR (CDCl₃) δ 1.2-1.6(6H, m), 1.6-1.95 (4H, m), 2.95 (2H, t), 3,42 (2H, t), 7.43 (2H, m) and7.90 (2H, m).

Intermediate A2 8-Hydroxy-1-(4-chlorophenyl)octan-1-one

To 8-bromo-1-(4-chlorophenyl)octan-1-one (4.0 g) in ethanol (170 ml) wasadded 3% aqueous sodium hydroxide (70 ml). The mixture was heated atreflux for 3 h, cooled and evaporated to one third volume. Water (50 ml)and dichloromethane (100 ml) were added. The organic layer was separatedand the aqueous layer was re-extracted with dichloromethane (2×50 ml).The combined extracts were washed with water (30 ml) and dried overmagnesium sulphate. The solvent was removed under reduced pressure andthe residue was crystallised from 40-60° C. petroleum ether to give8-hydroxy-1-(4-chlorophenyl)octan-1-one (1.0 g). ¹H-NMR (CDCl₃) δ1.25-1.9 (10H, m), 2.94 (2H, t), 3.64 (2H, t), 7.43 (2H, m) and 7.89(2H, m). (EI) Found M⁺=254. C₁₄H₁₉ClO₂ requires 254.

Intermediate A3 8-Bromo-1-(4-methoxyphenyl)octan-1-one

Prepared analogously to intermediate A1. ¹H-NMR (CDCl₃) δ 1.3-1.95 (10H,m), 2.91 (2H, t), 3.41 (2H, t), 3.87 (3H, s), 6.93 (2H, m) and 7.94 (2H,m).

Intermediate A4 8-Bromo-1-(4-bromophenyl)octan-1-one

Prepared analogously to intermediate A1. ¹H-NMR (CDCl₃) δ 1.25-1,.55(6H, m), 1.65-1.95 (4H, m), 2.93 (2H, t), 3.41 (2H, t), 7.60 (2H, m) and7.83 (2H, t).

Intermediate A5 8-Bromo-1-(2-thienyl)octan-1-one

Prepared analogously to intermediate A1, except using SnCl₄ as catalystin place of AlCl₃. ¹H-NMR (CDCl₃) δ 1.3-1.55 (6H, m), 1.65-1.95 (4H, m),2.90 (2H, t), 3.41 (2H, t), 3.41 (2H, t), 7.13 (1H, dd), 7.63 (1H, dd)and 7.70 (1H, dd).

Intermediate A6 8-Bromo-1-(2-furyl)octan-1-one

Prepared analogously to intermediate A1, except using SnCl₄ as catalystin place of AlCl₃. ¹H-NMR (CDCl₃) δ 1.3-1.55 (6H, m), 1.6-1.95 (4H, m),2.82 (2H, t), 3.41 (2H, t), 6.53 (1H, m), 7.18 (1H, m) and 7.58 (1H, m).

Intermediate A7 8-Bromo-1-(4-methylphenyl)octan-1-one

Prepared analogously to intermediate A1. ¹H-NMR (CDCl₃) δ 1.3-1.55 (6H,m), 1.65-1.95 (4H, m), 2.41 (3H, s), 2.94 (2H, t), 3.41 (2H, t), 7.25(2H, m) and 7.86 (2H, m).

Intermediate A8 8-Bromo-1-(4-fluorophenyl)octan-1-one

Prepared analogously to intermediate A1. ¹H-NMR (CDCl₃) δ 1.3-1.6 (6H,m), 1.6-1.95 (4H, m), 2.94 (2H, t), 3.41 (2H, t), 7.13 (2H, m) and 7.98(2H, m).

Intermediate A9 8-Bromo-1-(4-methyl-1-naphthyl)octan-1-one

Prepared analogously to intermediate A1. ¹H-NMR (CDCl₃) δ 1.3-1.55 (6H,m), 1.7-1.95 (4H, m), 2.74 (3H, s), 3.03 (2H, t), 3.41 (2H, t), 7.32(1H, m), 7.5-7.65 (2H, m), 7.76 (1H, d), 8.0-8.1 (1H, m) and 8.55-8.7(1H, m).

Intermediate A10 1-Bromo-8-(2-thiazolinyl)octane

To a solution of 2-methyl-2-thiazoline (1.01 g) in dry tetrahydrofuranat −70° C. was added a solution of n-butyl lithium in hexanes (2.5M, 4.0ml) dropwise over 10 min. After stirring at −70° C. for 2 h,1,7-dibromoheptane (12.9 g) was added in one portion (temperatureincreased to −45° C.). The mixture was cooled again to −70° C. for 1 hand then allowed to warm to room temperature over 1 h. The mixture wascooled to 0° C. and water (10 ml) added, followed by dilute hydrochloricacid (to pH 2). The organic layer was separated and the aqueous layerextracted with diethyl ethyl (2×20 ml). The organic layers were combinedand washed with water and brine and dried over magnesium sulfate.Evaporation under reduced pressure gave an oil that was chromatographedon silica gel using 40-60° C. petroleum ether:ethyl acetate 5:1 to give1-bromo-8-(2-thiazolinyl)octane (1.06 g). ¹H-NMR (CDCl₃) δ 1.2-1.5 (6H,m), 1.5-1.75 (4H, m), 1.75-1.95 (2H, m), 2.50 (2H, t), 3.28 (2H, t),3.40 (2H, t) and 4.21 (2H, dt).

Intermediate A11 1-Bromo-8-(2-pyridyl)octane

Prepared analogously to intermediate A10. ¹H-NMR (CDCl₃) δ 1.2-1.55 (8H,m), 1.6-1.95 (4H, m), 2.76 (2H, t), 3.41 (2H, t), 7.05-7.2 (2H, m),7.5-7.65 (1H, m) and 8.52 (1H, m).

Intermediate A12 8-(3,4-Dichlorophenyl)oct-7-yn-1-ol

A mixture of 3,4-dichloroiodobenzene (2.16 g), oct-7-yn-1-ol (1.20 g),tetrakis (triphenylphosphine)palladium (0) (0.185 g), copper (I) iodide(0.046 g) and triethylamine (15 ml) was stirred at room temperature for16 h. The solid was filtered off and the filtrate evaporated underreduced pressure. The residual oil was dissolved in ethyl acetate (15ml) and washed with water (10 ml), 2M hydrochloric acid (2×10 ml) andbrine (10 ml). Drying over magnesium sulfate and removal of the solventunder reduced pressure gave an oil that was purified by flashchromatography on silica gel using dichloromethane as eluent. This gave8-(3,4-dichlorophenyl)oct-7-yn-1-ol (1.89 g). ¹H-NMR (CDCl₃) δ 1.2-1.75(8H, m), 2.40 (2H, t), 3.66 (2H, t), 7.19 (1H, dd), 7.35 (1H, d) and7.47 (1H, dd).

Intermediate A13 8-(3,4-Dichlorophenyl)octan-1-ol

To a solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.70 g) inmethanol (20 ml) was added platinum dioxide (0.05 g) and the mixturereacted under an atmosphere of hydrogen (initial pressure 50 psi). After1 h. the catalyst was filtered through Hyflo and washed with methanol.The combined methanol layers were evaporated under reduced pressure togive 8-(3,4-dichlorophenyl)octan-1-ol (0.69 g). ¹H-NMR (CDCl₃) δ 1.1-1.8(12H, m), 2.55 (2H, t), 3.64 (2H, m), 6.99 (1H, dd) and 7.2-7.4 (2H, m).

Intermediate A14 8-Bromo-1-(3,4-dichlorophenyl)-1-octyne

A solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.52 g) in diethylether (2.5 ml) was treated with phosphorous tribromide (0.23 g) at 0° C.(ice/salt bath). The solution was stirred at 0-5° C. for 2 h and allowedto warm to room temperature. Aqueous sodium hydrogen carbonate solutionwas added. The aqueous layer was extracted with further diethyl ether(2×5 ml) and the combined organic layers were washed with brine (5 ml)and dried over magnesium sulfate. Removal of the solvent under reducedpressure gave an oil that was chromatographed on silica gel usingdichloromethane as eluent. This gave8-bromo-1-(3,4-dichlorophenyl)-1-octyne (0.25 g). ¹H-NMR (CDCl₃) δ1.35-1.7 (6H, m), 1.75-1.95 (2H, m), 2.33 (2H, t), 3.35 (2H, t), 7.13(1H, dd), 7.27 (1H, d) and 7.40 (1H, d).

Intermediate A15 1-Bromo-8-(3,4-dichlorophenyl)octane

A solution of 8-(3,4-dichlorophenyl)octan-1-ol (0.66 g) in 48%hydrobromic acid (7 ml) was stirred under reflux for 2 h. Water (20 ml)and diethyl ether (20 ml) were added. The organic layer was separatedand the aqueous layer reextracted with diethyl ether (10 ml). Thecombined organic extracts were washed with water (10 ml), sodiumhydrogen carbonate solution (10 ml) and brine (10 ml) and dried overmagnesium sulfate. The solution was treated with charcoal, filtered andevaporated under reduced pressure to give1-bromo-8-(3,4-dichlorophenyl)octane (0.74 g). ¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m), 2.55 (2H, t), 3.41 (2H, t), 7.00 (1H, dd), 7.25 (1H, dd) and7.33 (1H, d).

Intermediate A16 8-(3-Chlorophenyl)oct-7-yn-1-ol

Prepared analogously to intermediate A12. ¹H-NMR (CDCl₃) δ 1.25 (8H, m),2.41 (2H, t), 3.66 (2H, t), 7.13-7.33 (3H, m) and 7.37 (1H, m)

Intermediate A17 8-(3-Chlorophenyl)octan-1-ol

Prepared analogously to intermediate A13. ¹H-NMR (CDCl₃) δ 1.1-1.8 (12H,m), 2.57 (2H, t), 3.64 (2H, t), 7.0-7.4 (4H, m)

Intermediate A18 1-Bromo-8-(3-chlorophenyl)octane

Prepared analogously to intermediate A15. ¹H-NMR (CDCl₃) δ 1.05-1.9(12H, m), 2.50 (2H, t), 3.33 (2H, t) and 6.9-7.25 (4H, m).

Intermediate A19 8-(4-Acetylphenyl)octan-1-ol

Prepared analogously to intermediate A13. ¹H-NMR (CDCl₃) δ 1.2-1.8 (12H,m), 2.59 (3H, s), 2.68 (2H, t), 3.63 (2H, t) 7.25 (2H, m) and 7.88 (2H,m)

Intermediate A20 1-Bromo-8-(4-acetylphenyl)octane

Prepared analogously to intermediate A15. ¹H-NMR (CDCl₃) δ 1.2-1.75(10H, m), 1.85 (2H, m), 2.59 (3H, s), 2.67 (2H, m), 3.40 (2H, t),7.2-7.3 (2H, m) and 7.88 (2H, m).

Intermediate A21 1-Bromo-8-(4-fluorophenyl)octane

Triethylsilane (30.5 g, 260 mmol) was added dropwise to8-bromo-1-(4-fluorophenyl)octan-1-one (230 ml, 105 mmol) over 20 min,with cooling to keep the temperature at ca 30° C. After 2 hoursstirring, a further 3.1 g (27 mmol) triethylsilane was added, andreaction continued for an additional 2 hours. The mixture was pouredinto ice-water (200 ml) and ether (300 ml), then the organic layer waswashed with aqueous sodium hydroxide. dried and evaporated, finally at65° C./0.01 mm. The residue was filtered through silica gel, elutingwith petroleum ether, then distilled, collecting the fraction at122-140° C./0.5 mm (24.2 g). ¹H-NMR (CDCl₃) δ 1.2-1.7 (10H, m), 1.85(2H, m), 2.57 (2H, t), 3.40 (2H, t), 6.9-7.05 (2H, m) and 7.05-7.2 (2H,m).

Intermediate A22 1-Bromo-8-(4-methoxyphenyl)octane

Intermediate A23 1-Bromo-8-(4-pyridyl)octane

Prepared analogously to intermediate A10. ¹H-NMR (CDCl₃) δ 1.2-1.95(12H, m), 2.48 (2H, t), 3.42 (2H, t), 7.11 (2H, d) and 8.47 (2H, m).

Intermediate A24 1-Bromo-8-(4-chlorophenyl)octane

Prepared analogously to intermediate A21. ¹H-NMR (CDCl₃) δ 1.2-1.5 (8H,m), 1.5-1.7 (2H, m), 1.75-1.95 (2H, m), 2.56 (2H, t), 3.40 (2H, t), 7.08(2H, m) and 7.23 (2H, m).

Intermediate A25 1-Bromo-6-(4-chlorobenzyloxy)hexane

Sodium hydride (60%, 0.39 g) was added to a mixture of 6-bromohexanol(1.78 g) and 4-chlorobenzyl bromide (2.02 g) in dry tetrahydrofuran (150ml). The mixture was stirred at 25° C. for 5 h and poured into 1Mhydrochloric acid. Extraction with diethyl ether (3×), and washing thecombined extracts with water and brine gave a solution that was driedover magnesium sulfate and evaporated under reduced pressure. Theresidue so obtained was chromatographed on silica gel using 40-60° C.petroleum ether to 10% diethyl ether in 40-60° C. petroleum ether aseluents. This gave 1-bromo-6-(4-chlorobenzyloxy)hexane (1.7 g). ¹H-NMR(CDCl₃) δ 1.3-1.55 (4H, m), 1.55-1.7 (2H, m), 1.75-1.95 (2H, m),3.35-3.55 (4H, m), 4.46 (2H, s) and 7.2-7.4 (4H, m).

Intermediate A26 1-Bromo-6-(4-fluorobenzyloxy)hexane

Prepared analogously to intermediate A25. ¹H-NMR (CDCl₃) δ 1.3-1.5 (4H,m), 1.6 (2H, m), 1.9 (2H, m), 3.39 (2H, t), 3.45 (2H, t), 4.44 (2H, s),7.0-7.1 (2H, m), 7.2-7.4 (2H, m).

Intermediate A27 1-Bromo-6-benzyloxyhexane

Intermediate A28 1-Bromo-7-phenoxyheptane

To a mixture of phenol (0.58 g) and 1,7-dibromoheptane (4.76 g) indimethylformamide (5 ml) was added potassium carbonate (4.3 g) and themixture was heated at 80° C. for 6 h. The mixture was cooled and thesolvent was removed under reduced pressure. Toluene (10 ml) was addedand removed under reduced pressure. The residue was chromatographed onsilica gel using hexane as eluent. This gave 1-bromo-7-phenoxyheptane(1.15 g). ¹H-NMR (CDCl₃) δ 1.3-1.7 (6H, m), 1.7-2.1 (4H, m), 3.41 (2H,t), 3.95 (2H, t), 6.8-7.0 (3H, m) and 7.2-7.4 (2H, m).

Intermediate A29 1-Bromo-7-(4-chlorophenoxy)heptane

Prepared analogously to intermediate A28. ¹H-NMR (CDCl₃) δ 1.3-1.6 (6H,m), 1.7-2.0 (4H, m), 3.41 (2H, t), 3.91 (2H, t), 6.75-6.9 (2H, m) and7.15-7.3 (2H, m).

Intermediate A30 1-Bromo-7-(4-chlorophenylthio)heptane

To 1,7-dibromoheptane (23 g) and potassium carbonate (10 g) in drydimethylformamide (100 ml) was added 4-chlorothiophenol (4.3 g) dropwisewith stirring at 25° C. After 6 h, the mixture was filtered and thesolvent removed under reduced pressure. Chromatography of the residue onsilica gel using hexane as eluent gave1-bromo-7-(4-chlorophenylthio)heptane (9.6 g). ¹H-NMR (CDCl₃) δ 1.2-1.55(6H, m), 1.55-1.75 (2H, m), 1.8-2.0 (2H, m), 2.89 (2H, t), 3.40 (2H, t)and 7.2-7.4 (4H, m).

Intermediate A31 1-Bromo-7-(4-chlorophenylsulfinyl)heptane

A solution of 1-bromo-7-(4-chlorophenylthio)heptane (0.80 g) indichloromethane (10 ml) was cooled to −78° C. (cardice/acetone) and aslurry of metachloroperbenzoic acid (60%, 0.72 g) in dichloromethane (5ml) was added over 20min. After 40 min, the reaction was allowed to warmto room temperature and shaken with aqueous sodium sulfite/sodiumhydrogen carbonate solution. The organic layer was dried over magnesiumsulfate and evaporated under reduced pressure. The residue waschromatographed on silica gel using dichloromethane to 4% methanol indichloromethane as eluents to give1-bromo-7-(4-chlorophenylsulfinyl)heptane (0.43 g). ¹H-NMR (CDCl₃) δ1.2-2.0 (10H, m), 2.77 (2H, t), 3.39 (2H, t) and 7.4-7.7 (4H, m).

Intermediate A32 1-Bromo-7-(4-chlorophenylsulfonyl)heptane

To a solution of 1 -bromo-7-(4-chlorophenylthio)heptane (1.19 g) indichloromethane (20 ml) at −20° C. was added metachloroperbenzoic acid(60%, 2.23 g) portionwise over 15 min. The mixture was allowed to warmto room temperature over 1 h and was shaken with aqueous sodiumsulfite/sodium hydrogen carbonate solution. The organic layer was driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was chromatographed on silica gel using 50:50hexane:dichloromethane as eluent to give1-bromo-7-(4-chlorophenylsulfonyl)heptane (1.17 g). ¹H-NMR (CDCl₃) δ1.2-2.0 (10H, m), 3.07 (2H, m), 3.38 (2H, t), 7.5-7.6 (2H, m) and7.8-7.9 (2H, m).

Intermediate A33 1-Bromo-7-phenylthioheptane

Prepared analogously to intermediate A30. ¹H-NMR (CDCl₃) δ 1.2-1.55 (6H,m), 1.6-1.75 (2H, m), 1.75-1.95 (2H, m), 2.91 (2H, t), 3.40 (2H, t) and7.1-7.4 (5H, m).

Intermediate A34 1-Bromo-7-phenylsulfinylheptane

Prepared analogously to intermediate A31. ¹H-NMR (CDCl₃) δ 1.2-1.95(10H, m), 2.91 (2H, t), 3.40 (2H, m) and 7.1-7.4 (5H, m).

Intermediate A35 1-Bromo-7-phenylsulfonylheptane

Prepared analogously to intermediate A32. ¹H-NMR (CDCl₃) δ 1.2-2.0 (1H,m), 3.09 (2H, m), 3.38 (2H, t), 7.5-7.8 (3H, m) and 7.85-8.0 (2H, m).

Intermediate A36 8-Bromo-1-(4-chlorophenyl)-1-hydroxyoctane

To a solution of 8-bromo-1-(4-chlorophenyl)octan-1-one (0.95 g) inindustrial methylated spirit (10 ml) was added sodium borohydride (0.115g) at −10° C. After stirring for 1 h, glacial acetic acid (0.2 g) wasadded and the mixture was poured into water (60 ml) and extracted withdiethyl ether. The diethyl ether layer was washed with brine and driedover magnesium sulfate. Removal of the solvent under reduced pressuregave an oil that was chromatographed on silica gel using dichloromethaneas eluent. This gave 8-bromo-1-(4-chlorophenyl)-1-hydroxyoctane (0.70g). ¹H-NMR (CDCl₃) δ 1.15-1.95 (12H, m), 3.40 (2H, t), 4.65 (1H, t) and7.2-7.4 (4H, m).

Intermediate A37 9-Bromo-2-(4-fluorophenyl)-1-nonene

To a solution of butyl lithium (2.5M. 3.2 ml) in anhydroustetrahydrofuran (75 ml) was added triphenylmethylphosphonium bromide(2.86 g) in portions over 10 min. The mixture was stirred at 25° C. for3 h and a solution of 8-bromo-1-(4-fluorophenyl)octan-1-one (1.20 g) indry tetrahydrofuran (15 ml) added dropwise over 5 min. After stirring at25° C. for 1 h, the mixture was heated at reflux for 24 h. The mixturewas evaporated under reduced pressure and partitioned between diethylether (70 ml) and water (4×30 ml). The organic layer was washed withbrine and dried over magnesium sulfate. Removal of the solvent underreduced pressure gave an oil that was chromatographed on silica gelusing 5% diethyl ether in hexane. This gave9-bromo-2-(4-fluorophenyl)-1-nonene (0.75 g). ¹H-NMR (CDCl₃) δ 1.2-1.55(8H, m), 1.80 (2H, m), 2.46 (2H, t), 3.39 (2H, t), 5.03 (1H, bs), 5.20(1H, bs), 7.03 (2H, m) and 7.3-7.45 (2H, m).

Intermediate A38 1-(3-Chlorophenyl)hex-1-yn-6-ol

Prepared analogously to intermediate A12. ¹H-NMR (CDCl₃) δ 1.6-1.85 (4H,m), 2.45 (2H, bt), 3.71 (2H, t), 7.15-7.33 (3H, m) and 7.37 (1H, m).

Intermediate A39 6-(3-Chlorophenyl)hexan-1-ol

Prepared analogously to intermediate A13. ¹H-NMR (CDCl₃) δ 1.2-1.8 (8H,m), 2.58 (2H, t), 3.64 (2H, t) and 7.0-7.3 (4H, m).

Intermediate A40 1-Bromo-6-(3-chlorophenyl)hexane

Prepared analogously to intermediate A15. ¹H-NMR (CDCl₃) δ 1.2-1.95 (8H,m), 2.59 (2H, t), 3.40 (2H, t) and 7.0-7.3 (4H, m)

Intermediate A41 9-Bromo-1-(4-chlorophenyl)nonan-1-one

9-Bromononanoyl chloride was obtained from the carboxylic acid(reference 12) by treatment with thionyl chloride.9-Bromo-1-(4-chlorophenyl)nonan-1-one was prepared analogously tointermediate A1. ¹H-NMR (CDCl₃) δ 1.2-2.0 (12H, m), 2.95 (2H, t), 3.41(2H, t), 7.44 (2H, m) and 7.90 (2H, m).

Intermediate A42 N-(6-(4-Fluorophenyl)hexyl)-2-bromoacetamide

To a solution of 6-(4-fluorophenyl)-1-hexylamine (21.8 g) in drydichloromethane (200 ml) at 0° C. under an argon atmosphere was addeddiisopropylethylamine (14.4 g) followed by broimoacetyl bromide (22.5 g)over 30min whilst maintaining the temperature between 0-5° C. Theresulting orange solution was stirred at 0-5° C. for 45 min andevaporated to dryness. The residue was mixed with diethyl ether and thehydrobromide salt filtered off. The filtrate was evaporated underreduced pressure and the residue was chromatographed on silica gel using5:1 to 3:2 40-60° C. petroleum ether:ethyl acetate as eluents. This gavea yellow oil that was triturated with 40-60° C. petroleum ether,filtered and dried to give N-(1-(4-fluorophenyl)-hexyl) bromoacetamide(24.8 g). ¹H-NMR (CDCl₃) δ 1.25-1.45 (4H, m), 1.45-1.75 (4H, m), 2.57(2H, t), 3.28 (2H, q), 3.88 (2H ,s), 6.5 (1H, bs), 6.85-7.05 (2H, m) and7.05-7.2 (2H, m).

Intermediate A43 1-Bromo-4-(3-phenylpropyloxy)butane

Prepared as in reference 13.

Intermediate A44 6-(4-Chlorobenzoylamino)hexan-1-ol

To a solution of 6-amino-1-hexanol (12.9 g) and diisopropylethylamine(11.9 g) in dry dichloromethane (100 ml) at 5° C. was added4-chlorobenzoyl chloride (16.1 g) in dry dichloromethane at such a rateto maintain the temperature below 10° C. After stirring for 16 h, themixture was poured into water and filtered. The solid was washed withwater, 2M hydrochloric acid (150 ml), water, dichloromethane and wasdried under reduced pressure to give 6-(4-chlorobenzoylamino)hexan-1-ol(19.2 g). ¹H-NMR (d₆-DMSO) δ 1.25-1.65 (8H, m), 3.24 (2H, q), 3.38 (2H,t), 7.52 (2H, m), 7.84 (2H, m) and 8.54 (1H, bt)

Intermediate A45 1-Bromo-6-(4-chlorobenzoylamino)hexane

6-(4-Chlorobenzoylamino)hexan-1-ol (17.0 g) was refluxed in 48%hydrobromic acid (260 ml) for 2.5 h. The mixture was cooled and added towater (450 ml) and diethyl ether (450 ml). The organic layer was washedwith saturated sodium bicarbonate (450 ml) and brine (450 ml) and wasdried over magnesium sulfate. Evaporation followed by recrystallisationfrom diethyl ether gave 1-bromo-6-(4-chlorobenzoylamino)hexane (8.6 g).¹H-NMR (CDCl₃) δ 1.3-2.0 (8H, m), 3.35-3.55 (4H, m), 6.15 (1H, bs), 7.40(2H, m) and 7.70 (2H, m).

Intermediate B1 Ethyl 3-(5-pyrimidinyl)acrylate

A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g),palladium acetate (0.112 g), triphenyl phosphine (0.23 g) andtriethylamine (4.5 g) was stirred at 150° C. in a pressure vessel for 6hours. After cooling overnight, water (50 ml) was added to the darkresidue, and the product was extracted into toluene. Drying, charcoalingand evaporation gave a pale oil, which was triturated with pet, ether toobtain ethyl 3-(5-pyrimidyl)acrylate (4.78 g). ¹H-NMR (CDCl₃) δ 1.36(3H, t), 4.27 (2H, q), 6.59 (1H, d), 7.62 (1H, d), 8.88 (2H, s), 9.20(1H, s).

Intermediate B2 Ethyl 3-(5-pyrimidyl)propionate

To a solution of ethyl 3-(5-pyrimidyl)acrylate (4.75 g) in ethanol (90ml) was added 5% palladium on charcoal (0.2 g). The mixture washydrogenated at an initial pressure of 50 psi, then filtered to removecatalyst and the solvent evaporated. Water was added, and the productextracted into ether. Drying, charcoaling and evaporation gave ethyl3-(5-pyrimidyl)propionate (2.3 g) as a yellow oil. ¹H-NMR (CDCl₃) δ 1.23(3H, t), 2.69 (2H, t), 2.96 (2H, t), 4.14 (2H, q), 8.635 (2H, s) and9.09 (1H, s).

Intermediate B3 Ethyl 2-formyl-3-(5-pyrimidyl)propionate

A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and ethyl formate(1.41 ml) dissolved in dry dimethoxyethane (5 ml) was added dropwiseover 30 min to a suspension of sodium hydride (60%, 4.0 g) in DME (5 ml)under nitrogen, keeping the temperature below 0° C. Stirring wascontinued for a further 24 h, then the mixture was poured onto ice andwashed with ether. The aqueous layer was adjusted to pH 7, thenevaporated and the residue extracted with acetone. Filtration andevaporation gave crude product, which was taken up in ethyl acetate,charcoaled, dried and evaporated to give ethyl2-formyl-3-(5-pyrimidyl)propionate. Like other compounds of this type,this proved difficult to characterise and was used without furtherpurification.

Intermediate B4 3-(5-Pyrimidyl)acrylic acid

A mixture of 5-bromopyrimidine (100 g), acrylic acid (48 g),triphenylphosphine (2.5 g) and palladium II acetate (0.1 g) was refluxedin tri-n-butylamine (260 ml) with overhead stirring for 4.5 h at145-160° C. The mixture was cooled and a 10% solution of potassiumcarbonate (2 L) added followed by dichloromethane (500 mL). The organiclayer was separated and the aqueous phase extracted with diethyl ether(3×300 ml). The aqueous layer was brought to pH 3 with concentratedhydrochloric acid (ice-cooling) and the solid so formed was filtered anddried in vacuo to give 3-(5-pyrimidyl)acrylic acid (35 g). ¹H-NMR(d₆-DMSO) δ 6.82(1H, d), 7.60(1H, d) and 9.15(3H, 2xs)

Intermediate B5 Methyl 3-(5-pyrimidinyl)acrylate

3-(5-Pyrimidyl)acrylic acid (100 g) was added to a mixture of drymethanol (2 L) and 4M hydrogen chloride in dioxan (445 ml) and allowedto stir at 60° C. under argon for 18 h. The mixture was cooled, and thesolvent removed under reduced pressure. The residue was partitionedbetween dichloromethane (500 ml) and was washed with saturated sodiumbicarbonate (300 ml). The aqueous layer was extracted withdichloromrethane and the combined dichloromethane layers were dried overmagnesium sulfate and evaporated in vacuo to give methyl3-(5-pyrimidinyl)acrylate (85 g). ¹H-NMR (d₆-DMSO) δ 3.82(3H, s),7.03(1H, d), 7.75(1H, d) and 9.28(3H, s).

Intermediate B6 Methyl 3-(5-pyrimidyl)propionate

To a solution of methyl 3-(5-pyrimidyl)acrylate (85 g) in glacial aceticacid was added 10% palladium on charcoal (11.3 g) and ammonium formate(74.2 g) under argon. The mixture was heated at 110° C. for 20 min,cooled and the solvent removed in vacuo. The resulting oil was dissolvedin dichloromethane (1.5 L) and washed with saturated sodium bicarbonate(750 ml). The aqueous layer was extracted with further dichloromethane(200 ml), the organic layers were combined and dried over magnesiumsulfate. Removal of the solvent under reduced pressure gave an oil. Thiswas distilled under reduced pressure to give methyl3-(5-pyrimidyl)propionate (26 g). ¹H-NMR (CDCl₃) δ 2.69(2H, t), 2.97(2H,t), 3.70(3H, s), 8.65(2H, s) and 9.12(1H, s).

Intermediate B7 Methyl 2-(5-pyrimidyl)methyl)-3-methoxyacrylate

A mixture of methyl 3-(5-pyrimidyl)propionate (13.1 g) and methylformate (7.1 ml) dissolved in dry dimethoxyethane (20 ml) was addedportionwise to a suspension of sodium hydride (60%, 4.0 g) in DME (10ml) under argon. Reaction initiated rapidly and was stirred for afurther 2 h, diluted with dry diethyl ether (50 ml) and filtered. Thesolid so separated was washed with further diethyl ether (50 ml) and wasdried in vacuo to give a solid that was dissolved in dry dimethylformamide (50 ml) and potassium carbonate (11.3 g) added under argon. Asolution of dimethyl sulfate (7.0 ml) was, then added over 1 hour. Themixture was stirred for 18 h and the solvent removed in vacuo. Theresidue was partitioned between ethyl acetate (200 ml) and water (100ml). The aqueous layer was re-extracted with ethyl acetate (2×100 ml)and the combined ethyl acetate layers washed with brine (50 ml) anddried over sodium sulfate. The solvent was removed in vacuo to givemethyl 2((5-pyrimidyl)methyl)-3-methoxyacrylate (9.1 g).

Intermediate B8 2-(5-Pyrimidyl)methyl)-3-methoxyacrylic acid

To methyl 2-((5-pyrimidyl)methyl)-3-methoxyacrylate (9.0 g) was added,with stirring, a solution of sodium hydroxide (3.5 g) in water (43 ml)at RT under argon. After 20 h, the pH of the solution was brought to 3.5with concentrated hydrochloric acid. Sonication of the oil so formedgave 2-((5-pyrimidyl)methyl)-3-methoxyacrylic acid (5.4 g) as a paleyellow solid.

Intermediate B9 5-(Pyrimid-5-ylmethyl)-2-thiouracil

Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea (0.77 g)added, and the mixture stirred under reflux for 1 hour. A solution ofethyl 2-formyl-3-(5-pyrimidyl)propionate (1.99 g) in ethanol (5 ml) wasadded slowly, and reflux continued for 18 hours. The solvent wasevaporated, and the residue taken up in water and washed withdichloromethane. The aqueous solution was acidified to pH 5, and theprecipitate filtered off, washed with water and dried to obtain5-(pyrimid-5-ylmethyl)-2-thiouracil (0.71 g). ¹H-NMR (d6-DMSO) δ 3.58(2H, s), 7.54 (1H, s), 8.70 (2H, s) and 9.02 (1H, s). MPt 265-6° C.

Intermediate B10 5-((1-Benzyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared from methyl2-(1-benzyl-2-oxo-pyrid-4-yl)methyl)-3-hydroxyacrylate (reference 7)analogously to intermediate B9. ¹H-NMR (d6-DMSO) δ 5.04 (2H, s), 6.15(1H, dd), 6.21 (1H, bs), 7.2-7.4 (5H, m), 7.45 (1H, s) and 7.67 (1H, d);(EI) M=325. C₁₇H₁₅N₃O₂S requires 325.

Intermediate B11 5-((1-Methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared from methyl2-(1-methyl-2-oxo-pyrid-4-yl)methyl)-3-hydroxyacrylate (reference 7)analogously to intermediate B9. ¹H-NMR (CD₃OD) δ 3.50,3.51 (5H, 2xs),6.32 (1H, dd), 6.40 (1H, bs), 7.35 (1H, s) and 7.54 (1H, d).

Intermediate B12 5-((2,3-Dimethylpyrid-5-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B9. ¹H-NMR (d6-DMSO) δ 2.19 (3H,s), 2.35 (3H, s), 7.36 (2H, m) and 8.13 (1H, bs).

Intermediate B13 5-(Fur-2-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B9. ¹H-NMR (d₆-DMSO) δ 3.58 (2H,s), 6.11 (1H, m), 6.35 (1H, m), 7.27 (1H, s), 7.52 (1H, m), 12 41 (2H,br, m). Mpt 205-7° C. (dec)

Intermediate B14 5-(Pyrazin-2-ylmethyl)-2-thiouracil

Prepared from methyl 3-(2-pyrazinyl)propionate (reference 10)analogously to intermediate B9. ¹H-NMR (d₆-DMSO) δ 3.77 (2H, s), 7.48(1H, s), 8.46 (1H, d), 8.51 (1H, t) and 8.59 (1H, d). Mpt 265-7° C.(dec)

Intermediate B15 5-(Fur-3-ylmethyl)-2-thiouracil

Prepared from methyl 3-(3-furyl)propionate (reference 9) analogously tointermediate B9. ¹H-NMR (d6-DMSO) δ 3.33 (2H, s), 6.38 (1H, m), 7.19(1H, s) 7.47 (1H, m), 7.56 (1H, m). Mpt 197-9° C. (dec)

Intermediate B16 5-(Quinolin-3-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B9. ¹H-NMR (d6-DMSO) δ 3.77 (2H,s), 7.54 (2H, m), 7.71 (1H, m), 7.94 (2H, m), 8.14 (1H, m), 8.84 (1H, m)Mpt 274-9° C.

Intermediate B17 5-(2-(Pyrid-4-yl)ethyl)-2-thiouracil

Prepared analogously to intermediate B9. ¹H-NMR (d6-DMSO) δ 2.53 (2H,t), 2.77 (2H, t), 7.20 (3H, m) and 8.45 (2H, m). MPt 265-7° C. (dec)

Intermediate B18 5-(Pyrid-2-ylmethyl)-2-thiouracil

Prepared as in reference 2.

Intermediate B19 5-(Pyrid-3-ylmethyl)-2-thiouracil

Prepared as in reference 11.

Intermediate B20 5-(Pyrid-4-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B9. ¹H-NMR (d6-DMSO) δ 3.57 (2H,s), 7.25 (2H, m), 7.47 (1H, s), 8.44 (2H, m), 12.43 (2H, br, m)Mpt >250° C.

Intermediate B21 5-((2-Methylpyrid-5-yl)methyl)-2-thiouracil

Prepared as in reference 5.

Intermediate B22 5-(Thiazol-2-ylmethyl)-2-thiouracil

Prepared as in reference 2.

Intermediate B23 5-Benzyl-2-thiouracil

Prepared as in reference 6.

Intermediate B24 5-(Pyrid-3-ylmethyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 4.

Intermediate B255-(2-Methoxypyrid-4-ylmethyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 3.

Intermediate B265-(4-Methoxypyrid-2-ylmethyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 4.

Intermediate B275-((1-Butyl-2-oxo-pyrid-4-yl)methyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 7.

Intermediate B285-((1-Oxo-2-methylpyrid-5-yl)methyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 3.

Intermediate B295-((2,4-Dimethylpyrid-5-yl)methyl)-2-(nitroamino)pyrimidin-4-one

Prepared as in reference 8.

Intermediate B30 3-(1-Methylpyrazol-4-yl)acrylic acid

A mixture of 1-methylpyrazole-4-carboxaldehyde (made as in reference 15)(18.1 g), malonic acid (17.1 g), pyridine (15 ml) and piperidine (0.2ml) was heated to 100° C. for 1 hour. After cooling, water was added,followed by aqueous ammonia to obtain a clear solution, which wasacidified to pH5 with hydrochloric acid. The resulting solid wasfiltered off, washed with water and dried to obtain3-(1-methylpyrazol-4-yl)acrylic acid (18.9 g). ¹H-NMR (d₆-DMSO) δ 3.83(3H, s), 6.18 (1H, d), 7.44 (1H, d), 7.83 (1H, s), 8.07 (1H, s). (APCI)M+H=153. C₇H₈N₂O₂ requires 152.

Intermediate B31 Methyl 3-(1-methylpyrazol-4-yl)acrylate

3-(1-Methylpyrazol-4-yl)acrylic acid (18.86 g) was added to a solutionof sulphuric acid (15 ml) in methanol (150 ml), and the mixture refluxedfor 2 hours, cooled, and poured onto ice. The acid was neutralised withsolid sodium carbonate and the product extracted into dichloromethane,which was dried and evaporated. Crystallisation from ether/petrol gavemethyl 3-(1-methylpyrazol-4-yl)acrylate (16.0 g). ¹H-NMR (d₆-DMSO) δ3.77 (3H, s), 3.91 (3H, s), 6.16 (1H, d), 7.54 (1H, s), 7.56 (1H, d),7.69 (1H, s). (APCI) M+H=167. C₈H₁₀N₂O₂ requires 166.

Intermediate B32 Methyl 3-(1-methylpyrazol-4-yl)propionate

Prepared analogously to intermediate B6. ¹H-NMR (d₆-DMSO) δ 2.56 (2H,t), 2.79 (2H, t), 3.67 (3H, s), 3.85 (3H, s), 7.17 (1H, s), 7.31 (3H,s). (APCI) M+H=169. C₈H₁₂N₂O₂ requires 168.

Intermediate B33 Methyl 2-formyl-3-(1-methylpyrazol4-yl)propionate,sodium salt

Sodium hydride (2.62 g, 60% in oil) was washed with petrol and suspendedin dry dimethoxyethane (20 ml). Methyl3-(1-methylpyrazol-4-yl)propionate (8.8 g) and methyl formate (4.87 ml)were dissolved in DME (20 ml), and a few drops of the mixture added tothe sodium hydride suspension, which was warmed briefly to initiate thereaction before continuing dropwise addition at a rate which sustainedcontrolled evolution of hydrogen. The mixture was stirred for a further16 hours at room temperature, then diluted with ether. The solid wasfiltered off, washed with ether and immediately dried, and was usedpromptly without further purification.

Intermediate B34 5-((1-Methylpyrazol-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B9, except using the preformedsodium salt instead of adding sodium ethoxide. ¹H-NMR (d₆-DMSO) δ 3.33(3H, s), 3.75 (3H, s), 7.15 (1H, s), 7.23 (1H, s), 7.46 (1H, s), 12.2(1H, br s), 12.4 (1H, br s). (APCI) M+H=223. C₉H₁₀N₄OS requires 222.

Intermediate B35 Ethyl 3-(2-methoxypyrimidin-5-yl)acrylate

A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethylacrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84ml) were heated at 135° C. with stirring under argon for 12 h. Afterallowing to cool the solid mass was dissolved in water and ethylacetate, filtered, and the aqueous phase separated and further extractedwith ethyl acetate. The combined extracts were washed with saturatedaqueous ammonium chloride, dried (MgSO₄) and evaporated. The solid thusobtained was triturated with ether/light petrol (1:3, 350 ml), filtered,washed and dried, yield 52.41 g (63%). ¹H-NMR (CDCl₃) δ 1.33 (3H, t),4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s); MS(APCI+) found (M+H)=209; C₁₀H₁₂N₂O₃ requires 208.

Intermediate B36 Ethyl 3-(2-methoxypyrimidin-5-yl)propionate

A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10%palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. Thecatalyst was filtered off through hyflo and the filtrate evaporated. Theresidue was dissolved in dichloromethane, washed twice with saturatedaqueous ammonium chloride, dried (MgSO₄) and evaporated to an oil, yield41.2 g (78%). ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t),3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H)=211;C₁₀H₁₄N₂O₃ requires 210.

Intermediate B372-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid, mixedmethyl/ethyl esters

To a stirring suspension of sodium hydride (0.83 g of a 60% dispersionin oil) in anhydrous 1,2-dimethoxyethane (6 ml) was added dropwise asolution of methyl formate (1.54 ml) and ethyl3-(2-methoxypyrimid-5-yl)propionate (3.5 g) in anhydrous1,2-dimethoxyethane (6 ml) at such a rate as to maintain the reactiontemperature at 25-30° C. After 1 h, ether was added and the precipitatedoil allowed to settle. The solution was decanted off and replaced withfresh ether, and the oil slowly solidified. The solid2-(hydroxymethylene) derivative was filtered, washed and dried, yield3.8 g. A 1.33 g portion was suspended in dimethyl formamide (10 ml)together with anhydrous potassium carbonate (1.15 g), and a solution ofdimethyl sulphate (0.48 ml) in dimethylformamide (10 ml) was addeddropwise with stirring over 30 min. After 16 h the solvent wasevaporated and the residue treated with water and extracted with ethylacetate. The extracts were washed with water, dried (MgSO₄) andevaporated to give the product as an oil, yield 0.91 g. ¹H-NMR (CDCl₃) δ1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester), 3.88 (3H, s),3.97 (3H, s), 4.16 (2H, q), 7.39 (1H, s), 8.40 (2H, s), 3:2 ratio ofmethyl:ethyl esters. MS (APCI+) found (M+1)=253, 239 (ethyl and methylesters); C₁₂H₁₆N₂O₄ requires 252. C₁₁H₁₄N₂O₄ requires 238.

Intermediate B382-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid

A suspension of the mixed esters of intermediate 5 (0.9 g) in 2M aqueoussodium hydroxide (3.6 ml) was stirred at ambient temperature for 16 h togive a clear solution. This was diluted with water, extracted withdichloromethane and evaporated to about half volume, then acidified topH 3-4 (2M hydrochloric acid) when the product crystallised out. Thewhite solid was filtered, washed with ice-cold water and dried, yield0.46 g. ¹H-NMR (CDCl₃) δ 3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s,), 7.49(1H, s), 8.42 (2H, s); MS (APCI+) found (M+1)=225, C₁₀H₁₂N₂O₄ requires224.

Intermediate B39 5-(2-Methoxypyrimidin-5-ylmethyl)-2-thiouracil

To an ice cooled solution of potassium t-butoxide (7.83 g, 0.07 mol) inanhydrous THF (60 ml) was added dropwise with stirring under argon over1 hour to a solution of ethyl 3-(2-methoxypyrimidin-5-yl) propionate(5.87 g, 0.028 mol) and methyl formate (3.6 ml, 0.059 mol) in anhydrousether (70 ml). After stirring for 16 h, the solvents were evaporated,thiourea (4.25 g, 0.056 mol) and propan-2-ol (80 ml) added and themixture refluxed for 5 h. The solvent was evaporated and the residuedissolved in water, extracted twice with ether and acidified to pH 4.5with acetic acid. The solid which precipitated was filtered, washed wellwith water and dried, yield 5.57 g (80%). ¹H-NMR (d₆-DMSO) δ 3.47 (2H,s), 3.85 (3H, s), 7.43 (1H, s), 8.48 (2H, s), 12.25 (1H, br s), 12.46(1H, br s); MS (APCI+) found (M+H)=251; C₁₀H₁₀N₄O₂S requires 250.

Intermediate B40 5-(2-Benzyloxypyrimid-5-ylmethyl)-2-thiouracil

To a solution of benzyl alcohol (20 ml) in dry dimethylformamide (20 ml)was added sodium hydride ((60% in oil) 2.3 g) over 0.5 h under argon. Aslurry of 2-methoxypyrimidyl thiouracil (3.6 g) in dry dimethylformamide(10 ml) was added in one portion and the solution heated to 80° C. for2.5 h. After cooling, the solvent was removed under reduced pressure andthe residue partitioned between diethyl ether and water. The aqueouslayer was washed with further diethyl ether and then acidified to pH4with glacial acetic acid. The solid so formed was filtered, washed withwater and diethyl ether and dried in vacuo to give the desired material.¹H-NMR (d₆-DMSO) δ 3.49 (2H, s), 5.36 (2H, s), 7.2-7.5 (6H, m), 8.50(2H, s); MS (APCI+) found (M+1)=327; C₁₆H₁₄N₄O₂S requires 326.

Intermediate B41 Methyl 2-benzyl-3-methoxyacrylate

Prepared analogously to intermediate B7.

Intermediate B42 2-Benzyl-3-methoxyacrylic acid

Prepared analogously to intermediate B8.

Intermediate B43 Methyl2-(1-methyl-2-oxo-pyrid-4-yl)methyl)-3-methoxyacrylate

Prepared from methyl 3-(1-methyl-2-oxo-pyrid-4-yl)propionate (reference7) analogously to intermediate B7.

Intermediate B44 2-((1-Methyl-2-oxo-pyrid-4-yl)methyl)-3-methoxyacrylicacid

Prepared analogously to intermediate B8.

Intermediate B451-(Pyrid-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

2-((5-pyrimidyl)methyl)-3-methoxyacrylic arid (5.5 g) was slurried indry dichloromethane (100 ml) and oxalyl chloride (4.3 ml) added over 5min. After stirring at RT for 3 h, the solvent was removed in vacuo andthe residue triturated with toluene. The solvent was removed in vacuo togive a solid that was slurried in dry acetonitrile (100 ml) under Ar.Dried powdered potassium thiocyanate (3.25 g) was added in one portionat RT and the mixture was stirred for 15 h. Removal of the solvent invacuo gave a solid that was slurried with dry dimethylformamide (90 ml).One ninth of the slurry was added to triethylamine (0.42 ml) and2-pyridylmethylamine (0.49 g). The mixture was stirred for 19 h underargon and a solution of sodium ethoxide (3M) in ethanol (1.5 ml) wasadded in one portion. The mixture was heated on an oil bath (bath temp101° C.) for 2 h, cooled and the solvent removed under reduced pressure.The residue was dissolved in water (12 ml) and brought to pH 4 withglacial acetic acid. The solid so formed was filtered and dried in vacuoto give 1-(pyrid-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil (0.69g). ¹H-NMR (d₆-DMSO) δ 3.63(2H, s), 5.47(2H, s), 7.2-7.4(2H, m),7.7-7.85(1H, m), 8.04(1H, s), 8.5(1H, m), 8.7(2H, s) and 9.04(1H, s),(APCI) M+H=312. C₁₅H₁₃N₅OS requires 311.

Intermediate B461-(4-Hydroxycyclohexyl)-5-(pyrimid-5-ylmethyl)2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.0-2.0(8H,m), 3.63(2H, s), 8.10(1H, s), 8.72(2H, s) and 9.02(1H, s); (ES−) Found(M−1)=317. C₁₅H₁₈N₄O₂S requires 318.

Intermediate B471-(3-(1-Imidazolyl)prop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 2.22 (2H,m), 3.58 (2H, s), 4.13 (4H, m), 7.12 (1H, m), 7.36 (1H, m), 7.88 (1H,s), 8.08 (1H, s), 8.73 (2H, s), 9.05 (1H, s), 12.68 (1H, br s); (APCI+)Found (M+1)=329. C₁₅H₁₆N₆OS requires 328

Intermediate B481-(3-(1-Morpholino)prop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ2.35-2.6(6H+d5-DMSO, m), 3.4-3.8(6H+HOD, m), 4.19(2H, t), 7.96(1H, s),8.74(2H, s) and 9.04); (APCI+) Found (M+1)=348. C₁₆H₂₁N₅O₂S requires347.

Intermediate B491-(3-(2-Oxo-1-pyrrolidino)prop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.91 (4H,m), 2.20 (2H, t), 3.24 (2H, t), 3.37 (2H, t), 3.58 (2H, s), 4.09 (2H,t), 7.97 (1H, s), 8.74 (2H, s), 9.04 (1H, s); (APCI+) Found (M+1)=346.C₁₆H₁₉N₅O₂S requires 345

Intermediate B501-(3-Ethoxycarbonylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.17(1H,t), 1.98(2H, m), 2.34(2H, t), 3.59(2H, s), 4.04(2H, q), 4.16(2H, t),7.90(1H, s), 9.03(1H, s); (ES+) Found (M+1)=335. C₁₅H₁₈N₄O₃S requires334.

Intermediate B511-(3-Dimethylaminoprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 2.21(6H,s), 3.60(2H, s), 4.15(2H, t), 7.91(1H, s), 8.72(2H, s), 9.03(1H, s);(APCI+) Found (M+1)=306. C₁₄H₁₉N₅O₂S requires 305.

Intermediate B521-(3-Hydroxyprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.85(2H,m), 3.45(2H, b), 3.61(2H, s), 4.19(2H, t), 4.65(1H, bs), 7.85-8.0(2H,m), 8.71(2H, s) and 9.04(1H, s); (APCI) M+H=279. C₁₂H₁₄N₄O₂S requires278.

Intermediate B53 1-(3-Hydroxyprop-1-yl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.85(2H,m), 3.46(2H, m), 3.56(2H, s), 4.19(2H, t), 4.65(1H, t), 7.1-7.4(5H, m)and 7.81(1H, s); (FAB) M+H=277. C₁₄H₁₆N₂O₂S requires 276.

Intermediate B541-(3-Methoxyprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.94(2H,m), 3.21(3H, s), 8.55(2H, s), 4.20(2H, t), 7.88(1H, s), 8.72(2H, s) and9.03(1H, s); (ES−) Found (M−1)=291. C₁₉H₂₂BrClN₂O₂S requires 292.

Intermediate B551-(3-Phenylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 2.04(2H,m), 2.63(2H, t), 3.58(2H, s), 4.18(2H, t), 7.1-7.35(5H, m), 7.92(1H, s),8.72(2H, s) and 9.03(1H, s); (APCI+) Found (M+1)=339. C₁₈H₁₈N₄OSrequires 338.

Intermediate B561-(5-Hydroxypent-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ (HOAc salt)1.79(3H, s), 3.59(2H, s), 4.13(2H, t), 7.96(1H, s), 8.72(2H, s) and9.02(1H, s); (APCI+) Found (M+1)=307. C₁₄H₁₈N₄O₂S requires 306.

Intermediate B57 1-(Pyrid-2-ylmethyl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.59(2H,s), 5.49(2H, s), 7.1-7.45(7H, m), 7.79(1H, m), 7.95(1H, s) and 8.51(1H,m); MPt 171-4° C.; (EI) M=309. C₁₇H₁₅N₃OS requires 309.

Intermediate B581-(Pyrid-3-ylmethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.11 (3H,s), 3.15 (2H, s), 5.21 (2H, s), 5.86 (1H, m), 5.95 (1H, m), 7.15 (1H,m), 7.34 (1H, m), 7.52 (1H, m), 7.80 (1H, s), 8.26 (1H, m), 8.34 (1H,m), 12.55 (1H, br, s); (APCI+) Found (M+1)=341. C₁₇H₁₆N₄OS requires 340

Intermediate B591-(Pyrid-3-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.49 (2H,s), 5.33 (2H, s), 7.28 (1H, m), 7.64 (1H, m), 7.97 (1H, s), 8.42 (2H,m), 8.59 (2H, s), 8.88 (1H, m), 12.70 (1H, br. s) Mpt>250° C.

Intermediate B60 1-(Pyrid-3-ylmethyl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.57(2H,s), 5.46(2H, s), 7.1-7.35(5H, m), 7.40(1H, m), 7.75(1H, s), 8.02(1H, s),8.51(1H, m) and 8.59(1H, m). MPt 236-8° C.; (EI) M=309. C₁₇H₁₅N₃OSrequires 309.

Intermediate B611-(Pyrid-4-ylmethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.39(3H,s), 5.45(2H, s), 6.11(1H, dd), 6.21(1H, m), 7.25(2H, m), 7.58(1H, d),7.96(1H, s) and 8.54(2H, m). MPt 181-3° C.; (EI) M=340. C₁₇H₁₆N₄O₂Srequires 340.

Intermediate B621-(Pyrid-4-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.64 (2H,s), 5.45 (2H, s), 7.28 (2H, m), 8.00 (1H, s), 8.55 (2H, m), 8.73 (2H,m), 9.05 (1H, m), 12.85 (1H, br s) Mpt>250° C.

Intermediate B63 1-(Pyrid-4-ylmethyl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.58(2H,s), 5.46(2H, s), 7.1-7.4(7H, m), 7.93(1H, s) and 8.54(2H, m); MPt 174-6°C.; (EI) M=309. C₁₇H₁₅N₃OS requires 309.

Intermediate B64 1-(Pyrid-4-ylmethyl)-2-thiouracil

Prepared from 3-methoxyacrylic acid, analogously to intermediate B45.¹H-NMR (d₆-DMSO) δ 5.45(2H, s), 6.03(2H, d), 7.23(2H, m), 7.94(2H, d)and 8.54(2H, m); MPt 267-70° C.; (EI) M=219. C₁₀H₉N₃OS requires 219.

Intermediate B651-(2-(Pyrid-2-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.22(2H,t), 3.51(2H, s), 4.51(2H, t), 7.25(2H, m), 7.7(2H, m), 8.47(1H, m),8.61(2H, s) and 9.03(1H, s); (APCI+) Found (M+1)=326. C₁₆H₁₅N₅OSrequires 325.

Intermediate B661-(2-(Pyrid-3-yl)ethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.08 (2H,t), 3.29 (2H, s), 3.37 (3H, s), 4.38 (2H, t), 5.96 (1H, m), 6.13 (1H,m), 7.34 (1H, m), 7.60 (1H, m), 7.67 (1H, m), 7.71 (1H, s), 8.46 (2H,m), 12.73 (1H, br. s); (APCI+) Found (M+1)=355. C₁₈H₁₈N₄O₂S requires 354

Intermediate B671-(2-(Pyrid-3-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.08(2H,t), 3.53(2H, s), 4.36(2H, t), 7.3(1H, m), 7.65(1H, m), 7.78(1H, s),8.45(2H, bs), 8.65(2H, s) and 9.05(1H, s); (APCI+) Found (M+1)=326.C₁₆H₁₅N₅OS requires 325.

Intermediate B681-(2-(Pyrid-4-yl)ethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.07 (2H,t), 3.30 (2H, s), 3.37 (3H, s), 4.39 (2H, t), 5.94 (1H, m), 6.15 (1H,m), 7.27 (2H, m), 7.56 (1H, m), 7.72 (1H, s), 8.48 (2H, m), 12.72 (1H,br. s); (APCI+) Found (M+1)=355. C₁₈H₁₈N₄O₂S requires 354

Intermediate B691-(2-(Pyrid-4-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.16(2H,t), 3.54(2H, s), 4.45(2H, t), 7.48(2H, d), 7.82(1H, s), 8.60(2H, d),8.67(2H, s) and 9.05(1H, s); (ES+) Found (M+1)=326. C₁₆H₁₅N₅OS requires325.

Intermediate B701-(2-Phenylethyl)-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.04(2H,t), 3.27(3H, s), 4.35(2H, t), 5.93(1H, m), 6.12(1H, bs), 7.1-7.45(5H,m), 7.56(1H, d) and 7.67(1H, s); MPt 230-3° C.; (APCI) M+H=354.C₁₉H₁₉N₃O₂S requires 353.

Intermediate B71Benzyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.38(s),5.44(2H, s), 6.07(1H, m), 6.18(1H, m), 7.1-7.5(5H, m), 7.57(1H, d) and7.96(1H, s). (EI) M=339. C₁₈H₁₇N₃O₂S requires 339.

Intermediate B72 1,5-Dibenzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 3.63(2H, s),5.35(2H, s), 6.84(1H, s) and 7.05-7.45(10H, m). MPt 151-2° C.; (EI)M=308. C₁₈H₁₆N₂OS requires 308.

Intermediate B73 1-(2-Thienylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.60 (2H,s), 5.58 (2H, s), 7.03 (1H, m), 7.26 (1H, m), 7.50 (1H, m), 8.08 (1H,s), 8.69 (2H, s), 9.04 (1H, s), 12.18 (1H, br s) (APCI+) Found(M+1)=317. C₁₄H₁₂N₄OS₂ requires 316

Intermediate B741-(2,2-Dimethylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 0.96(9H,s), 3.62(2H, s), 4.17(2H, s), 7.77(1H, s), 8.73(2H, s) and 9.04(1H, s);(APCI+) Found (M+1)=291. C₁₄H₁₈N₄OS requires 290.

Intermediate B751-(2-(1-Piperidino)ethyl)-5-(pyrimid-5-ylmethyl)-2thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.28-1.72(6H, m), 2.50 (4H, m), 2.73 (2H, t), 3.61 (2H, s), 4.29(2H, t), 7.80(1H, s), 8.73 (2H, s), 9.05 (1H, s), 12.71 (1H, br s); (APCI+) Found(M+1)=332. C₁₆H₂₁N₅OS requires 331

Intermediate B761-(2-Acetylaminoethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.75(3H,s), 3.43(2H, m), 3.61(2H, s), 4.18(2H, t), 7.78(1H, s), 8.03(1H, bt),8.73(2H, s) and 9.03 (1H, s); (ES+) Found (M+1)=306. C₁₃H₁₅N₅O₂Srequires 305.

Intermediate B77 1-(2-Hydroxyethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.60(2H,s), 3.72(2H, bq), 4.21(2H, t), 4.99(1H, t), 7.83(1H, s), 8.73(2H, s) and9.03(1H, s); (ES+) Found (M+1)=265. C₁₁H₁₂N₄O₂S requires 264.

Intermediate B78 1-(2-Hydroxyethyl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.55(2H,s), 3.71(2H, bm), 4.20(2H, t), 4.99(1H, bs), 7.1-7.45(5H, m) and7.70(1H, s); MPt 171.3-3° C.; (FAB) M+H=263. C₁₃H₁₄N₂O₂S requires 262.

Intermediate B791-Dimethylaminocarbonylmethyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 2.86 (3H,s), 3.02 (3H, s), 3.61 (2H, s), 5.09 (2H, s), 7.76 (1H, s), 8.71 (2H,s), 9.05 (1H, s); (APCI+) Found (M+1)=306. C₁₃H₁₅N₅O₂S requires 305

Intermediate B801-Ethoxycarbonylmethyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.19 (3H,t), 3.62 (2H, s), 4.16 (2H, q), 4.94 (2H, s), 7.88 (1H, s), 8.73 (2H,s), 9.06 (1H, s); (APCI+) Found (M+1)=307. C₁₃H₁₄N₄O₃S requires 306

Intermediate B81 1-(Fur-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.62 (2H,s), 5.43 (2H, s), 6.47 (2H, m), 7.66 (1H, m), 7.98 (1H, s), 8.70 (2H,s), 9.04 (1H, s), 12.75 (1H, br s); (APCI+) Found (M+1)=301. C₁₄H₁₂N₄O₂Srequires 300

Intermediate B82 1-(Fur-2-ylmethyl)-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.57(2H,s), 5.43(2H, s), 6.45(2H, s), 7.1-7.4(5H, m), 7.66(1H, m) and 7.85(1H,s); MPt 153-5° C.; (FAB) M+H=299. C₁₆H₁₄N₂O₂S requires 298.

Intermediate B831-Methyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.57(3H,s), 6.12(1H, m), 6.20(1H, bs), 7.57(1H, d) and 7.87(1H, s); (EI) M=263.C₁₂H₁₃N₃O₂S requires 263.

Intermediate B84 1-Methyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.33(3H,s), 7.93(1H, s) 8.73(2H, s) and 9.02(1H, s); (APCI) M+H=235. C₁₀H₁₀N₄OSrequires 234.

Intermediate B85 1-Methyl-5-benzyl-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 3.55(2H, s),3.57(3H, s), 7.1-7.4(5H, m) and 7.84(1H, s); MPt 143-6° C.; (EI) M=232.C₁₂H₁₂N₂OS requires 232.

Intermediate B861-Phenyl-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 3.51(3H+MeOH,s), 6.16(1H, m), 6.48(1H, m), 7.1-7.45(4H, m) and 7.45-7.65(3H, m); (EI)M=325; C₁₇H₁₅N₃O₂S requires 325.

Intermediate B87 1-(2-Methoxyethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 3.26 (3H, s),3.60 (2H, s), 3.65 (2H, t), 4.33 (2H, t), 7.83 (1H, s), 8.70 (2H, s),9.04 (1H, s); (ES+) M+H=279; C₁₂H₁₄N₄O₂S requires 278.

Intermediate B881-(2-Methylprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. (APCI) M−H=275. C₁₃H₁₆N₄OSrequires 276.

Intermediate B89 1-Ethyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.23 (3H,t), 3.60 (2H, s), 4.19 (2H, q), 7.95(1H, s) 8.73(2H, s) and 9.04(1H, s);(APCI) M−H=247. C₁₁H₁₂N₄OS requires 248.

Intermediate B90 1-(8-Phenyloctyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ1.15-1.4(8H, m), 1.45-1.8(4H, m), 2.56(2H, t), 3.6 (2H, s), 4.11(2H, t),7.1-7.35(5H, m), 7.94(1H, s), 8.73(2H, s) and 9.02(1H, s). (APCI)M+H=409. C₂₃H₂₈N₄OS requires 408.

Intermediate B91 1-(9-Phenylnonyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ1.15-1.4(8H, m), 1.45-1.8(4H, m), 2.55(2H, t), 3.58 (2H, s), 4.12(2H,t), 7.1-7.35(5H, m), 7.95(1H, s), 8.72(2H, s) and 9.02(1H, s), (APCI)M+H=421. C₂₄H₃₀N₄OS requires 422.

Intermediate B92 1-Undecyl-5-(2-ethoxypyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆ DMSO) δ 0.8-0.95(3H, m), 1.05-1.5 (19H, m), 1.6-1.8 (2H, m), 3.49 (2H, s), 4.11 (2H, t),4.31 (2H, q), 8.48 (2H, s); MS (APCI+) found (M+1)=418; C₂₂H₃₄N₄O₂Srequires 417.

Intermediate B93 1-(2-Phenylethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ3.00-3.10 (2H, t), 3.50 (2H, s), 4.29-4.40 (2H, t), 7.10-7.33 (5H, m),7.71 (1H, s), 8.68 (2H, s), 9.00 (1H, s), 12.62-12.75 (1H, br.s); MS(APCI−) found (M−1)=323; C17H16N4OS requires 324.

Intermediate B94 1-Benzyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ 3.57(2H, s), 4.46 (2H, s), 7.10-7.44 (6H, m), 7.91 (1H, s), 8.69 (2H, s),9.01 (1H, s); MS (APCI+) found (M+1)=311; C₁₆H₁₄N4OS requires 310.

Intermediate B95 1-Undecyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ0.79-0.93 (3H, t), 1.12-1.44 (16H, m), 1.60-1.79 (2H, t), 3.59 (2H, s),4.05-4.20 (2H, t), 7.96 (1H, s), 8.70 (2H, s), 9.01 (1H, s), 12.61 (1H,s), MS (APCI−) found (M−1)=373; C₂₀H₃₀N₄OS requires 374.

Intermediate B96 1-Dodecyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ0.79-0.94 (3H, t), 1.13-1.47 (18H, s), 1.60-1.80 (2H, br.t), 3.59 (2H,s), 4.06-4.20 (2H, t), 7.96 (1H, s), 8.71 (2H, s), 9.03 (1H, s); MS(ES−) found (M−1)=387; C₂₁H₃₂N₄OS requires 388.

Intermediate B971-(2-(Thien-2-yl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ3.17-3.47 (2H, t), 3.52 (2H, s), 4.30-4.43 (2H, t), 6.80-7.04 (2H, m),7.27-7.40 (1H, m), 7.73 (1H, s), 8.62 (2H, s), 9.03 (1H, s) 11.97-12.5(1H, br.s); MS (APCI−) found (M−1)=329; C₁₅H₁₄N₄OS₂ requires 330.

Intermediate B981-(5-Methylfuran-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ 2.24(3H, s), 3.63 (2H, s), 5.37 (2H, s), 6.01-6.08 (1H, d), 6.30-6.38 (1H,d), 7.92 (1H, s), 8.72 (2H, s), 9.04 (1H, s) 12.73 (1H, s), MS (ES−)found (M−1)=313; C₁₅H₁₄N₄O₂S requires 314.

Intermediate B99 1-(4-Fluorobenzyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ 3.60(2H, s), 5.41 (2H, s), 7.13-7.25 (2H, m), 7.35-7.47 (2H, m), 8.02 (1H,s), 8.70 (2H, s), 9.03 (1H, s), 12.78 (1H, s); MS found (M−1)=327;C₁₆H₁₃FN₄OS requires 328.

Intermediate B1001-(2-(2-Chlorophenyl)ethyl)-5-(Pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ3.12-3.22 (2H, t), 3.49 (2H, s), 4.34-4.46 (2H, t), 7.14-7.43 (4H, m),7.52 (1H, s), 8.57 (2H, s), 9.04 (1H, s), 11.40-11.85 (1H, br.s); MS(APCI−) found (M−1)=357; C₁₇H₁₅ClN₄OS requires 358.

Intermediate B101 1-(2-Phenoxyethyl)-5-(Pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ 3.63(2H, s), 4.25-4.37 (2H, t), 4.50-4.60 (2H, t), 6.84-7.00 (3H, m),7.20-7.33 (2H, t), 7.94 (1H, s), 8.71 (2H, s), 9.06 (1H, s), 12.78 (1H,s); MS (ES+) found (M+1)=341; C₁₇H₁₆N₄O₂S requires 340.

Intermediate B1021-(5-Ethoxycarbonylpent-1-yl)-5-(Pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.10-1.20 (3H, t), 1.21-1.39 (2H, m), 1.45-1.80 (4H, m), 2.22-2.38 (2H,m), 3.59 (2H, s), 3.96-4.19 (4H, m), 7.94 (1H, s), 8.70 (2H, s), 9.03(1H, s), 12.12-12.35 (1H, br.s); MS (ES−) found (M−1) 361; C₁₇H₂₂N₄O₃Srequires 362.

Intermediate B1031-(1-Ethoxycarbonylethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.06-1.30 (3H, t), 1.58-1.70 (3H, d), 3.67 (2H, d), 4.02-4.27 (2H, m),6.02-6.19 (1H, q), 8.05 (1H, s), 8.70 (2H, s), 9.03 (1H, s), 12.80 (1H,s); MS (APCI+) found (M+1)=321; C₁₄H₁₆N₄O₃S requires 320.

Intermediate B104 1-(1-Methylethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.26-1.45 (6H, d), 3.65 (2H, s), 5.53-5.74 (1H, m), 8.10 (1 h, s), 8.72(2H, s), 9.02 (1H, s), 12.60 (1H, s); MS (APCI−) found (M+1)=261;C₁₂H₁₄N₄OS requires 262.

Intermediate B105 1-Cyclopropyl-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ0.92-1.10 (4H, m), 3.37-3.43 (1H, m), 3.60 (2H, s), 7.89 (1H, s), 8.71(2H, s), 9.02 (1H, s), 12.60 (1H, s); MS (APCI−) found (M−1)=259;C₁₂H₁₂N₄OS requires 260.

Intermediate B1061-(1-Ethoxycarbonylcycloprop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.05-1.20 (3H, t), 1.40-1.95 (4H, m), 3.61 (2H, s), 4.02-4.18 (2H, q),7.98 (1H, s), 8.72 (2H, s), 9.04 (1H, s), 12.04 (1H, s); MS (APCI+)found (M+1)=333; C₁₅H₁₆N₄OS requires 332.

Intermediate B1071-(4-Ethoxycarbonylbenzyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.23-1.38 (3H, t), 3.60 (2H, s), 4.24-4.40 (2H, q), 5.50 (2H, s),7.35-7.47 (2H, m), 7.86-8.00 (2H, m), 8.04 (1H, s), 8.70 (2H, s), 9.03(1H, s), 12.07-12.40 (1H, br.s); MS (APCI−) found (M−1)=381; C₁₉H₁₈N₄O₃Srequires 382.

Intermediate B1081-(4-Methoxycarbonylcyclohex-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.32-1.92 (6H, m), 2.10-2.30 (2H, m), 2.67-2.80 (1H, m), 3.64 (3H, s),3.69 (2H, s), 5.17-5.34 (1H, br.s), 7.87 (1H, s), 8.70 (2H, s), 9.01(1H, s), 12.63 (1H, s); MS (APCI−) found (M−1)=359; C₁₇H₂₀N₄O₃S requires360.

Intermediate B1091-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. Solid. ¹H-NMR (DMSO) δ1.14-1.60 (12H, m), 3.60 (2H, s), 3.62-3.70 (2H, t), 4.26-4.35 (2H, t),7.00-7.12 (2H, t), 7.14-7.24 (2H, m), 7.80 (1H, s), 8.70 (2H, s), 9.00(1H, s), 12.64-12.77 (1H, br.s); MS (APCI−) found (M−1)=441;C₂₃H₂₇FN₄O₂S requires 442.

Intermediate B1101-Undecyl-5-(1-methyl-2-oxopyrid-4-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 0.88 (3H, t),1.26 (14H, m), 1.32 (2H, t), 1.75 (2H, m), 3.48 (2H, s), 3.52 (3H, s),4.11 (2H, t), 6.10 (1H, m), 6.40 (1H, s), 7.08 (1H, s), 7.22 (1H, d),9.56 (1H, bs); MS (APCI+) M+1=404, C₂₂H₃₃N₃O₂S requires 403. MPt137-140° C. (cream solid)

Intermediate B1111-(3-Ethoxycarbonylpropyl)-5-(1-methyl-2-oxopyrid-4-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.17 (3H,t), 1.95 (2H, m), 2.35 (2H, m), 3.34 (5H, m), 4.03 (2H, q), 4.17 (2H,m), 6.11 (1H, m), 6.20 (1H, s), 7.57 (1H, d), 7.83 (1H, s), 12.63 (1H,bs); MS (APCI+) M+1=3642, C₁₇H₂₁N₃O₄S requires 363. MPt 168-170° C.(cream solid).

Intermediate B1121-(2-(4-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 0.85 (3H,m), 1.25 (4H, m), 1.53 (2H, m), 2.52 (2H, m), 2.99 (2H, m), 3.49 (2H,s), 4.33 (2H, m), 7.03-7.24 (4H, m), 7.71 (1H, s), 8.59 (2H, s), 9.03(1H, s), 12.70 (1H, bs); MS (APCI+) M+1=395, C₂₂H₂₆N₄OS requires 394.(light brown solid)

Intermediate B1131-(2-(4-Pent-2-en-1-ylphenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 0.89 (3H,m), 1.30-1.60 (2H, m), 2.24 (2H, m), 3.03 (2H, m), 3.51 (2H, s), 4.35(2H, m), 5.63 (1H, m), 6.33 (1H, s), 7.10-7.33 (4H, m),7.76 (1H, s),8.61 (2H, s), 9.03 (1H, s), 12.70 (1H, bs); MS (APCI+) M+1=393,C₂₂H₂₄N₄OS requires 392. (light brown solid)

Intermediate B1141-(2-(4-Bromophenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.02 (2H,t), 3.53 (2H, s), 4.33 (2H, t), 7.22 (2H, m), 7.49 (2H, m), 7.77 (1H,s), 8.60 (2H, s), 9.02 (1H, s), 12.7 (1H, bs), MS (APCI+) M+1=403,C₁₇H₁₅BrN₄OS requires 402

Intermediate B115 1-(4-Bromobenzyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 3.60 (2H,s), 5.39 (2H, s), 7.29 (2H, d), 7.57 (2H, d), 8.01 (1H, s), 8.70 (2H,s), 9.03 (1H, s), 12.75 (1H, bs), MS (APCI+) M+1-389, C₁₆H₁₃BrN₄OSrequires 388

Intermediate B1161-(2-(3-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 0.89 (3H, m),1.30 (4H, m), 1.55 (2H, m), 2.53 (2H, t), 3.10 (2H, t), 3.42 (2H, s),4.35 (2H, t), 6.49 (1H, s), 6.91-7.22 (4H, m), 8.44 (2H, s), 9.11 (1H,s), 9.60 (1H, bs) MS(APCI+) M+1=395, C₂₂H₂₆N₄OS requires 394. MPt 137.5°C. (colourless solid)

Intermediate B1171-(2-(2-Pent-1-ylphenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (CDCl₃) δ 0.88 (3H, t),1.28 (4H, m), 1.49 (2H, m), 2.50 (2H, t), 3.15 (2H, t), 3.42 (2H, s),4.34 (2H, t), 6.41 (1H, s), 7.03-7.21 (4H, m), 8.50 (2H, s), 9.12 (1H,s), 9.70 (1H, bs); MS(APCI+) M+1=395, C₂₂H₂₆N₄OS requires 394. MPt181.6° C. (pale orange solid)

Intermediate B1181-(3-Ethoxycarbonylphenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (CDCl₃) δ: 1.41 (t,3H), 3.70 (s, 2H), 4.41 (q, 2H), 7.30 (s, 1H), 7.35 (m, 1H), 7.60 (m,2H), 7.98 (m, 1H), 8.15 (d, 1H), 8.71 (s, 2H), 9.10 (s, 1H). MS (ES+)Found (M+1)=369; C₁₈H₁₆N₄O₃S requires 368.

Intermediate B1191-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (CDCl₃) δ: 1.41 (t,3H), 3.69 (s, 2H), 4.39 (q, 2H), 7.30 (s, 1H), 7.46 (d, 2H), 8.21 (d,2H), 8.72 (s, 2H), 9.10 (s, 1H). MS (ES+) Found (M+1)=369; C₁₈H₁₆N₄O₃Srequires 368.

Intermediate B1201-(5-(Ethoxycarbonyl)fur-2-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (CDCl₃) δ: 1.39 (t,3H), 3.69 (s, 2H), 4.39 (q, 2H), 6.69 (d, 1H), 7.28 (d, 1H), 7.41 (s,1H), 8.72 (s, 2H), 9.12 (s, 1H). MS (APCI+) Found (M+1)=359; C₁₆H₁₄N₄O₄Srequires 358.

Intermediate B1211-Phenyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (CDCl₃) δ: 3.69 (s,2H), 7.30 (m, 3H), 7.50 (m, 3H), 8.72 (s, 2H), 9.10 (s, 1H). MS (ES+)Found (M+1)=297; C₁₅H₁₂N₄OS requires 296.

Intermediate B1221-(4-(tert-Butoxycarbonylamino)but-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (DMSO-d₆) δ: 1.37 (s,9H), 1.4 (m, 2H), 1.65 (m, 2H), 2.93 (m, 2H), 3.59 (s, 2H), 4.13 (t,2H), 6.81 (br s, 1H), 7.49 (s, 1H), 8.70 (s, 2H), 9.04 (s, 1H), 13.45(br s, 1H). MS (ES+) Found (M+1) 392; C₁₈H₂₅N₅O₃S requires 391.

Intermediate B1231-(3-(Ethoxycarbonylamino)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45 as a pale buff solid. 1H NMR(DMSO-d₆) δ: 1.15 (t, 3H), 1.85 (m, 2H), 3.02 (m, 2H), 3.59 (s, 2H),4.01 (q, 2H), 4.14 (t, 2H), 7.12 (br s, 1H), 7.93 (s, 1H), 8.69 (s, 2H),9.00 (s, 1H), 13.55 (br s, 1H). MS (APCI+) Found (M+1)=350; C₁₅H₁₉N₅O₃Srequires 349.

Intermediate B1241-(1-Undecyl)-5-(2-methoxypyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45, except using sodium methoxidein place of ethoxide. ¹H-NMR (CDCl₃) δ 0.8-0.95 (3H, t), 1.1-1.85 (18H,m), 3.59 (2H, s), 4.01 (3H, s), 4.11 (2H, t), 7.04 (1H, s), 8.43 (2H,s); MS (APCI+) found (M+1)=405; C₂₁H₃₂N₄O₂S requires 404.

Intermediate B1251-(4-(Dec-1-yl)phenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. The ethoxide cyclisation stepfailed to go to completion, but the crude thiouracil was used in thenext step without purification.

Intermediate B1261-(4-(Non-1-yloxyphenyl))-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125

Intermediate B1271-(4-(Hex-1-yl)phenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125

Intermediate B1281-(3-(Non-1-yloxy)phenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125

Intermediate B1291-(3-(Dec-1-yl)phenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125

Intermediate B130 1-(4-Iodophenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125

Intermediate B131 1-(2-Fluorobenzyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (d₆-DMSO) δ 3.62 (2H,s), 5.45 (2H, s), 7.1-7.4 (4H, m), 7.98 (1H, s), 8.70 (2H, s), 9.04 (1H,s), 12.8 (1H, bs), MS (APCI−) M−1=327, C₁₆H₁₃FN₄OS requires 328

Intermediate B132(S)-1-(Tetrahydrofur-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (d₆-DMSO) δ 1.5-1.65(1H, m), 1.75-2.05 (3H, m), 3.62 (2H, s), 3.65 (1H, m), 3.79 (1H, m),3.95 (1H, m), 4.24 (1H, m), 4.47 (1H, dd), 7.83 (1H, s), 8.70 (2H, s),9.04 (1H, s), 12.7 (1H, bs), MS (APCI−) M−1=303, C₁₄H₁₆N₄O₂S requires304

Intermediate B133(R)-1-(Tetrahydrofur-2-ylmethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H NMR (d₆-DMSO) δ 1.5-1.65(1H, m), 1.75-2.05 (3H, m), 3.62 (2H, s), 3.65 (1H, m), 3.79 (1H, m),3.95 (1H, m), 4.24 (1H, m), 4.47 (1H, dd), 7.83 (1H, s), 8.70 (2H, s),9.04 (1H, s), 12.7 (1H, bs), MS (APCI−) M−1=303, C₁₄H₁₆N₄O₂S requires304

Intermediate B1341-(2-(4-Methoxyphenyl)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 2.97 (2H,t), 3.51 (2H, s), 3,74 (3H, s), 4.31 (2H, t), 6.85 (2H, m), 7.49 (2H,m), 7.14 (1H, s), 8.59 (2H, s), 9.03 (1H, s), 12.7 (1H, bs), MS (APCI+)M+1=355, C₁₈H₁₈N₄O₂S requires 354

Intermediate B1351-(Undec-1-yl)-5-(2-methylpyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45, except using sodium methoxidein place of ethoxide. ¹H-NMR (CDCl₃) δ 0.8-0.9 (3H, t), 1.2-1.35 (16H,m), 1.75 (2H, m), 2.73 (3H, s), 3.62 (2H, s), 4.11 (2H, t), 7.05 (1H,s), 8.57 (2H, s), 9.7-9.8 (1H, br s); MS (APCI+) found (M+1)=389;C₂₁H₃₂N₄OS requires 388.

Intermediate B136 1-(4-Acetylphenyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B125.

Intermediate B1371-(trans-4-(Methoxycarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d₆-DMSO) δ 1.0-1.4(4H, m), 1.65 (2H, m), 1.92 (2H, m), 2.15-2.35 (1H, m), 3.58 (3H, s),3.60 (2H, s), 4.01 (2H, m), 7.88 (1H, s), 8.70 (2H, s), 9.06 (1H, s),12.6 (1H, br s); MS (APCI−) found (M−1)=373; C18H22N4O3S requires 374.

Intermediate B1381-(2-(t-Butoxycarbonylamino)ethyl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d6-DMSO) δ 1.34 (9H,s), 3.32 (2H, m), 3.58 (2H, s), 4.19 (2H, m), 6.99 (1H, t), 7.69 (1H,s), 8.71 (2H, s), 9.03 (1H, s), 12.6 (1H, br s); MS (APCI−) found(M−1)=362; C₁₆H₂₁N₅O₃S requires 363.

Intermediate B1391-(3-(5-Phenylpent-1-yloxy)prop-1-yl)-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared analogously to intermediate B45. ¹H-NMR (d6-DMSO) δ 1.33 (2H,m), 1.4-1.7 (4H, m), 1.95 (2H, m), 2.55 (2H, t), 3.2-3.5 (4H, m), 3.60(2H, s), 4.18 (2H, t), 7.1-7.3 (5H, m), 7.86 (1H, s), 8.71 (2H, s), 9.03(1H, s), 12.6 (1H, br s); MS (APCI+) found (M+1)=425; C₂₃H₂₈N₄O₂Srequires 424.

General method A: S-Alkylation of thiouracils

A1 (N1-unsubstituted thiouracils). Sodium (2.2 equiv) was dissolved inethanol to give a ca. 0.5M solution of sodium ethoxide. The appropriatethiouracil (1 equiv) was added, usually giving a clear solution, thenthe appropriate alkyating agent was added (1.0-1.25 equiv were used invarious preparations, but no consistent advantage was seen with higheramounts) and the mixture was stirred at room temperature overnight. Theethanol was removed by evaporation, the residue was taken up in water,and the solution adjusted to pH 5 with acetic acid. In many cases theproduct precipitated, and was filtered off, washed with water and dried.When necessary, the aqueous solution was extracted with ethyl acetate,the organic layers dried and evaporated, and the residue triturated withether or pet, ether to obtain the product.

A2. A mixture of thiouracil (1 equiv), the appropriate alkylating agent(1-1.1 equiv) and diisopropylethylamine (1-1.1 equiv) was stirredovernight at room temperature in dichloromethane (12 ml/mmol). Thesolution was diluted with dichloromethane and washed with saturatedsodium bicarbonate solution. The organic layer was added directly to asilica gel column. Elution (ethyl acetate to methanol:ethyl acetate)gave the desired product.

A3. A mixture of thiouracil (1 equiv), the appropriate alkylating agent(1-1.1 equiv) and diisopropylethylamine (1-1.1 equiv) was stirred for 1h at between 64 and 72° C. in 1,2-dichloroethane (12 ml/mmol). Thesolution was diluted with dichloromethane and washed with saturatedsodium bicarbonate solution. The organic layer was added directly to asilica gel column. Elution (ethyl acetate to methanol:ethyl acetate)gave the desired product.1

A4. A mixture of the appropriate thiouracil (1 equiv), the appropriatealkylating agent (1.1 equiv) and potassium carbonate (2-3 equiv) in drydimethylformamide (ca 4 ml/mmol) was heated at 65° C. for 2.5 h. Themixture was cooled, the solvent was removed under reduced pressure andthe residue partitioned between dichloromethane (50 ml) and 3% aqueouspotassium carbonate solution. The organic layer was applied directly toa SepPak cartridge (10 g, Silica) and elution was continued with 2% to8% methanol in ethyl acetate as eluent. This gave 1-(4hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one(0.1 8 g)

A5. Array synthesis. This proceeded essentially as in method A1, exceptthat parallel reactions were carried out in screw-capped polypropylenetubes. The appropriate thiouracil (1 equiv) was weighed into each tube,then 0.5M ethanolic sodium ethoxide (2 equiv) and the appropriate alkylhalide (1 equiv) as an 0.5M ethanol solution were dispensed in bypipette and the tubes capped and vortexed at room temperature overnighton an orbital shaker. After removal of solvent in a vacuum centrifuge,individual products were worked up in the usual way.

General method B: Displacement of 2-(nitroamino)pyrimidones with thiols

The appropriate 2-(nitroamino)pyrimidone (1 equiv) and thiol (2 equiv)in pyridine (ca 2 ml per mmol) were stirred at reflux for 2 days, thenthe pyridine was evaporated. Trituration with an appropriate solvent, asdescribed in the individual examples, gave the desired product.

General method C: N1-Alkylation of pyrimidin-4-ones

C1. To a stirred solution of the pyrimidinone (1 equiv) in dry DMF (20ml) was added sodium hydride (1 equiv). The mixture was stirred at roomtemperature for 30 min, then the appropriate alkylating agent (1-1.1equiv) was added in portions over 15 min, and the mixture was stirredovernight. Ethyl acetate and dilute hydrochloric acid were added, theorganic layer was separated and washed with water and brine, dried andevaporated. Flash chromatography (silica, 1-10% methanol indichloromethane) gave first a mixture of the 3-alkyl and4-alkoxypyrimidine byproducts, then the desired 1-alkylpyrimidin-4-one.

C2. A mixture of pyrimidinone (1 equiv), the appropriate alkylatingagent (1-1.1 equiv) and diisopropylethylamine (1-1.5 equiv, usually1.25-1.3 equiv) was stirred for between 20-72 h at room temperature indichloromethane (12 ml/mmol) (if the pyrimidinone was only partiallysoluble in dichloromethane, dimethylformamide (2 ml/mmol) was alsoadded). The solution was diluted with dichloromethane containing up to2% methanol (if dimethylformamide was used, the solvent was firstremoved under reduced pressure) and washed with saturated ammoniumchloride solution and sodium bicarbonate solution. The organic layer wasseparated and added directly to a silica gel column. Elution (ethylacetate to methanol:dichloromethane:ethyl acetate) gave the desiredproduct.

C3. Similar to method C2, except that the solvent was 1,2-dichloroethanein place of dichloromethane, and the pyrimidone was treated withtributyltin chloride (1 equiv) and stirred overnight to form the silylether before addition of the alkylating agent.

General method D: Ester hydrolysis

To a solution of the ester (1 equiv) in 1,4 dioxane (9 ml/mmol) underargon was added a solution of sodium hydroxide (0.95-1 equiv) in water(2-4.5 ml/mmol) whilst keeping the temperature below 25° C. Afterstirring for between 2-20 h at room temperature (the reaction waschecked for completion), 75% of the solvent was removed under reducedpressure at <25° C. The residue was diluted with water and brought topH3 with 5% aqueous sodium bisulphate. The solid so formed was filteredand dried in vacuo to give the desired material.

General method E: Amide coupling

To a slurry/solution of the carboxylic acid (1 equiv) in dichloromethane(or dimethylformamide) (12 ml/mmol) was added hydroxybenzotriazole (0.1equiv), the amine (1 equiv) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 eq).After stirring under argon for 24 h, (the solvent removed under reducedpressure if dimethylformamide) the mixture was diluted withdichloromethane and washed with saturated sodium bicarbonate. Additionof the organic layer directly to a silica gel column and elution (ethylacetate to methanol:ethyl acetate) gave the desired product.Alternatively, the crude product could be purified by solid phaseextraction on a BondElut SCX cartridge, eluted withdichloromethane/methanol.

General method F: Urea synthesis

The appropriate BOC-protected amine was dissolved in neat TFA (ca 5ml/g) at room temperature. After 5min the solution was concentrated to abrown gum and re-evaporated from ethyl acetate. The crude amine salt indichloromethane (ca 15 ml/g) was treated with the isocyanate (1.1equiv.) in dichloromethane, followed by the addition of triethylamineand the reaction mixture shaken overnight. The reaction mixture wascentrifuged to remove any solid material and the supernatent washed withwater. The organic layer was dried over anhydrous magnesium sulfate andthe solution concentrated. The crude material was then purified bysilica gel chromatography.

Example 12-(8-Phenyloct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B10 by general method A1 as a white solid.MPt 124-129° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5 (8H, m), 1.5-1.8 (4H, m),2.59 (2H, t), 3.13 (2H, t), 3.54 (2H, s), 5.10 (2H, s), 6.14 (1H, dd),6.50 (1H, bs), 7.15-7.4 (11H, m) and 7.68 (1H, s).

Example 22-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B10 and A21 by general method A5 as a whitesolid. MPt 147-151° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5 (8H, m), 1.5-1.8 (4H,m), 2.58 (2H, t), 3.15 (2H, t), 3.55 (2H, s), 5.10 (2H, s), 6.15 (1H,dd), 6.47 (1H, m), 6.95 (2H, t), 7.05-7.2 (3H, m), 7.25-7.45 (5H, m) and7.67 (1H, s); MS (EI) M=531; C₃₁H₃₄FN₃O₂S requires 531.

Example 32-(8-(4-Chlorophenyl)oct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B10 and A24 by general method A5 as a whitesolid. MPt 160-164° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (12H, m), 2.56 (2H, t),3.13 (2H, t), 3.55 (2H, s), 5.10 (2H, s), 6.15 (1H, m), 6.48 (1H, bs),7.0-7.45 (10H, m) and 7.67 (1H, s); MS (EI) M=547; C31H34ClN3O2Srequires 547.

Example 42-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B10 and A1 by general method A5 as a whitesolid. MPt 147-151° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (10H, m), 2.93 (2H, t),3.13 (2H, t), 3.55 (2H, s), 5.10 (2H, s), 6.15 (1H, dd), 6.49 (1H, bs),7.05-7.5 (8H, m), 7.68 (1H, s) and 7.89 (2H, d); MS (EI) M=561;C₃₁H₃₂ClN₃O₃S requires 561.

Example 52-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B10 and A8 by general method A5 as a whitesolid. MPt 125-133° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (10H), 2.93 (2H, t),3.13 (2H, t), 3.55 (2H, s), 5.10 (2H, s), 6.15 (1H, m), 6.48 (1H, bs),7.05-7.45 (8H, m), 7.68 (1H, s) and 7.97 (2H, m); MS (EI) M=545;C₃₁H₃₂FN₃O₃S requires 545.

Example 62-(9-Phenylnon-1-yl)thio-5-((1-benzyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B10 by general method A5 as a white solid.MPt 127-132° C,; ¹H-NMR (CDCl₃) δ 1.2-1.9 (14H, m), 2.58 (2H, t), 3.14(2H, t), 3.55 (2H, s), 5.10 (2H, s), 6.15 (1H, dd), 6.48 (1H, bd),7.05-7.4 (10H, m) and 7.67 (1H, s); MS (EI) M=527; C₃₂H₃₇N₃O₂S requires527.

Example 72-(6-Phenylhex-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B11 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (4H, m), 1.6 (4H, m), 2.55 (2H, t), 3.08 (2H, t), 3.35 (3H, s), 3.41(2H, s), 6.10 (1H, dd), 6.16 (1H, d), 7.1-7.3 (5H, m), 7.55 (1H, d),7.78 (1H, s).

Example 82-(7-Phenylhept-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B11 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (6H, m), 1.6 (4H, m), 2.55 (2H, t), 3.07 (2H, t), 3.35 (3H, s), 3.41(2H, s), 6.10 (1H, dd), 6.15 (1H, d), 7.1-7.3 (5H, m), 7.55 (1H, d),7.77 (1H, s).

Example 92-(8-Phenyloct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B11 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (8H, m), 1.6 (4H, m), 2.55 (2H, t), 2.97 (2H, t), 3.40 (3H, s), 3.42(2H, s), 6.25 (1H, dd), 6.29 (1H, d), 7.1-7.3 (5H, m), 7.52 (1H, d),7.58 (1H, s).

Example 102-(9-Phenylnon-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B11 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (10H, m), 1.6 (4H, m), 2.55 (2H, t), 3.06 (2H, t), 3.34 (3H, s),6.10 (1H, dd), 6.15 (1H, d), 7.1-7.3 (5H, m), 7.55 (1H, d), 7.75 (1H,s).

Example 112-(6-Benzyloxyhex-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B11 and A27 by general method A5. ¹H-NMR(d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6 (2H, m), 3.08 (2H, t), 3.40(2H, t), 3.64 (2H, m), 4.43 (2H, s), 6.09 (1H, dd), 6.15 (1H, d),7.1-7.3 (5H, m), 7.55 (1H, d), 7.75 (1H, s).

Example 122-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B11 and A1 by general method A5 as a whitesolid. MPt 125-127° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m),3.00 (2H, t), 3.08 (2H, t), 3.35 (3H, s), 3.41 (2H, s), 6.10 (1H, m),6.15 (1H, s), 7.57 (3H, m), 7.79 (1H, s), 7.97 (1H, s), 7.97 (2H, d).

Example 132-(8-Phenyloct-1-yl)thio-5-((1-butyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B27 by general method B as a white solid frompet. ether. ¹H-NMR (d₆-DMSO) δ 0.87 (3H, t), 1.26 (10H, m), 1.5-1.7 (6H,m), 2.55 (2H, t), 3.08 (2H, t), 3.42 (2H, s), 3.79 (2H, t), 6.1 (2H, m),7.2 (3H, m), 7.3 (2H, m), 7.54 (1H, d), 7.81 (1H, s), 12.8 (1H, br s).

Example 142-(8-Phenyloct-1-yl)thio-5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B12 by general method A1 as a light brownsolid. MPt 111-113° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m),2.18 (3H, s), 2.35 (3H, s), 2.51 (2H, t), 3.05 (2H, t), 3.52 (2H, s),7.1=7.3 (5H, m), 7.34 (1H, d), 7.74 (1H, s), 8.14 (1H, d).

Example 152-(6-Benzyloxyhex-1-yl)thio-5-((2,3-dimethylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B12 and A27 by general method A1 as a lightbrown solid. MPt 100-102° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H,m), 1.6 (2H, m), 2.18 (3H, s), 2.35 (3H, s), 3.06 (2H, t), 3.36 (2H, t),3.52 (2H, s), 4.43 (2H, s), 7.3 (6H, m), 7.74 (1H, s), 8.14 (1H, d).

Example 162-(8-Phenyloct-1-yl)thio-5-((2,4-dimethylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B29 by general method B as a beige solid fromether/pet. ether. MPt 73-75° C.; ¹H-NMR (d₆-DMSO) δ 1.2 (8H, m), 1.6(4H, m), 2.21 (3H, s), 2.37 (3H, s), 2.57 (2H, t), 3.06 (2H, t), 3.57(2H, s), 6.83 (1H, s), 7.1-7.3 (5H, m), 7.51 (1H, s), 8.15 (1H, s), 12.8(1H, br s).

Example 172-(5Phenylpent-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A1 as a white solid.MPt 113-117° C,; ¹H-NMR (d₆-DMSO) δ 1.35 (2H, m), 1.6 (4H, m), 2.40 (3H,s), 2.55 (2H, t), 3.07 (2H, t), 3.57 (2H, s), 7.1-7.3 (6H, m), 7.52 (1H,dd), 7.78 (1H, s), 8.33 (1H, d).

Example 182-(N-(6-(4-Fluorophenyl)hexyl)carboxamidomethyl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A42 by general method A1. MPt159-161° C.; ¹H-NMR (d₆-DMSO) δ 1.2 (4H, m), 1.4 (2H, m), 1.5 (2H, m),2.40 (3H, s), 2.52 (2 H, t), 3.04 (2H, m), 3.57 (2H, s), 3.81 (2H, s),7.0-7.2 (5H, m), 7.49 (1H, dd), 7.75 (1H, s), 8.15 (1H, t), 8.33 (1H,dd).

Example 192-(6-Benzyloxyhex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A27 by general method A1. MPt 93-95°C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6 (2H, m), 2.40 (3H,s), 3.07 (2H, t), 3.40 (2H, t), 3.57 (2H, s), 4.43 (2H, s), 7.13 (1H,d), 7.3 (5H, m), 7.51 (1H, dd), 7.80 (1H, s), 8.34 (1H, d).

Example 202-(8-Phenyloct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A5 as a white solid.MPt 92-94° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.40 (3H,s), 2.55 (2H, t), 3.02 (2H, t), 3.54 (2H, s), 7.11 (1H, d), 7.16 (3H,m), 7.25 (2H, m), 7.50 (1H, m), 7.69 (1H, s), 8.33 (1H, d).

Example 212-(7-Phenylhept-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A5 as a white solid.MPt 101-103° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m), 2.40 (3H,s), 2.55 (2H, t), 3.02 (2H, t), 3.54 (2H, s), 7.11 (1H, d), 7.16 (3H,m), 7.25 (2H, m), 7.50 (1H, m), 7.68 (1H, s), 8.33 (1H, d).

Example 222-(6-Phenylhex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A1 as a white solid.MPt 104-106° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.6 (4H, m), 2.40 (3H,s), 2.55 (2H, t), 3.05 (2H, t), 3.57 (2H, s), 7.1-7.3 (6H, m), 7.50 (1H,m), 7.78 (1H, s), 8.33 (1H, d).

Example 232-(9-Phenylnon-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A1 as a white solid.MPt 112-114° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (10H, m), 1.6 (4H, m), 2.40 (3H,s), 2.54 (2H, t), 3.05 (2H, t), 3.55 (2H, s), 7.1-7.3 (6H, m), 7.50 (1H,m), 7.88 (1H, s), 8.33 (1H, d).

Example 242-(6-(4-Chlorobenzyloxy)hex-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A25 by general method A1 as a whitesolid. MPt 93-95° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6(2H, m), 2.51 (3H, s), 3.13 (2H, t), 3.44 (2H, t), 3.70 (2H, s), 4.45(2H, s), 7.06 (1H, d), 7.3 (3H, m), 7.53 (1H, dd), 7.64 (1H, s), 8.43(1H, d).

Example 252-(6-(4-Fluorobenzyloxy)hex-1-yl)thio-5-((2-methylpyrid-5yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A26 by general method A1 as a whitesolid. MPt 90-92° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6(2H, m), 2.51 (3H, s), 3.13 (2H, t), 3.45 (2H, t), 3.70 (2H, s), 4.44(2H, s), 7.0 (3H, m), 7.3 (2H, m), 7.53 (1H, dd), 7.64 (1H, s), 8.43(1H, d).

Example 262-(8-(4-Methoxyphenyl)-8-oxooct-1-yl)thio-5((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A3 by general method A1 as a whitesolid. MPt 114-116° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m),2.40 (3H, s), 2.93 (2H, t), 3.08 (2H, t), 3.57 (2H, s), 3.83 (3H, s),7.02 (2H, d), 7.13 (1H, d), 7.51 (1H, dd), 7.79 (1H, s), 7.93 (2H, d),8.34 (1H, d), 12.7 (1H, br s).

Example 272-(8-(4-Methoxyphenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A22 by general method A1 as a whitesolid. MPt 103-105° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.4-1.7 (4H, m),2.40 (3H, s), 2.48 (2H, t), 3.07 (2H, t), 3.57 (2H, s), 3.84 (3H, s),6.82 (2H, d), 7.07 (2H, d), 7.12 (1H, d), 7.51 (1H, dd), 7.78 (1H, s),8.34 (1H, d), 12.7 (1H, br s).

Example 282-(8-(4-Fluorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A21 by general method A1. ¹H-NMR(d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.40 (3H, s), 2.53 (2H, t), 3.06(2H, t), 3.56 (2H, s), 7.0-7.2 (5H, m), 7.5 (1H, m), 7.77 (1H, s), 8.33(1H, m).

Example 292-(8-(4-Fluorophenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A8 by general method A1. ¹H-NMR(d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m), 2.40 (3H, s), 3.00 (2H, t), 3.08(2H, t), 3.57 (2H, s), 7.13 (1H, d), 7.34 (2H, m), 7.51 (1H, dd), 7.80(1H, s), 8.04 (2H, m), 8.34 (1H, d), 12.7 (1H, br s).

Example 302-(8-(4-Chlorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A24 by general method A1 as a whitesolid. MPt 100-102° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m),2.40 (3H, s), 2.57 (2H, t), 3.06 (2H, t), 3.56 (2H, s), 7.12 (1H, d),7.20 (2H, d), 7.31 (2H, d), 7.50 (1H, dd), 7.76 (1H, s), 8.33 (1H, d).

Example 312-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A1 by general method A1 as a whitesolid. MPt 90-92° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m), 2.40(3H, s), 3.00 (2H, t), 3.07 (2H, t), 3.56 (2H, s), 7.12 (1H, d), 7.51(1H, dd), 7.58 (2H, d), 7.86 (1H, s), 7.97 (2H, d), 8.34 (1H, d).

Example 322-(8-Phenyl-8-oxooct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A1 as a white solid.MPt 72-74° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m), 2.40 (3H,s), 3.00 (2H, t), 3.08 (2H, t), 3.57 (2H, s), 7.13 (1H, m), 7.5 (3H, m),7.6 (1H, m), 7.80 (1H, s), 7.94 (1H, m), 8.33 (1H, d), 12.6 (1H, br s).

Example 332-(8-(4-Chlorophenyl)-8-hydroxyoct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A36 by general method A1. ¹H-NMR(d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.40 (3H, s), 3.08 (2H, t), 3.58(2H, s), 4.5 (1H, br t), 4.9 (1H, br s), 7.10 (1H, m), 7.31 (4H, m),7.48 (1H, m), 7.71 (1H, s), 8.32 (1H, m), 12.4 (1H, br s).

Example 342-(8-(4-Methylphenyl)-8-oxooct-1-yl)thio-5-((2methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediates B21 and A7 by general method A1 as a whitesolid. MPt 115-116° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (10H, m), 2.41 (3H, s),2.51 (3H, s), 2.93 (2H, t), 3.13 (2H, t), 7.06 (1H, m), 7.25 (2H, m),7.26 (1H, s), 7.54 (1H, m), 7.85 (2H, m) and 8.43 (1H, d); MS (EI)M=449; C₂₆H₃₁N₃O₂S requires 449.

Example 352-(4-Phenylbut-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method A1. Mpt 129-30° C.;¹H-NMR (d₆-DMSO) δ 1.6 (4H, m), 2.40 (3H, s), 2.58 (2H, m), 3.11 (2H,m), 3.57 (2H, s), 7.1-7.3 (6H, m), 7.52 (1H, dd), 7.80 (1H, s), 8.33(1H, d).

Example 362-(8-Phenyloct-1-yl)thio-5-((1-oxo-2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B28 by general method B. Trituration withether and recrystallisation from ethyl acetate gave the product as anoff-white solid. MPt 93-95° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H,m), 2.55 (2H, t), 3.07 (2H, t), 3.56 (2H, s), 7.1-7.3 (6H, m), 7.52 (1H,dd), 7.78 (1H, s), 8.33 (1H, d).

Example 372-(8-Phenyloct-1-yl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B25 by general method B as a beige solid fromethanol. MPt 70-72° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m),2.55 (2H, t), 3.08 (2H, t), 3.58 (2H, s), 3.80 (3H, s), 6.64 (1H, s),6.84 (1H, d), 7.1-7.3 (5H, m), 7.80 (1H, s), 8.02 (1H, d).

Example 382-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrazin-2-pyrimidin-4-one

Prepared from intermediates B14 and A1 by general method A1 as a whitesolid. MPt 122.5-124° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8(4H, m), 3.00 (2H, t), 3.10 (2H, t), 3.81 (2H, s), 7.59 (2H, d), 7.8(1H, bs), 7.97 (2H, d), 8.46 (1H, m), 8.50 (1H, m) and 8.58 (1H, m); MS(FAB) M+1=457; C23H25ClN4O2S requires 456.

Example 39 2-(8-Phenyloct-1-yl)thio-5-(pyrid-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B18 by general method A1. ¹H-NMR (d₆-DMSO) δ1.3 (8H, m), 1.6 (4H, m), 2.55 (2H, t), 3.09 (2H, t), 3.76 (2H, s),7.1-7.3 (7H, m), 7.67 (1H, m), 7.74 (1H, s), 8.44 (1H, m), 12.7 (1H, brs).

Example 402-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(thiazol-2-ylmethyl)pyrimidin-4-one

Prepared from intermediates B22 and A1 by general method A1 as a palebuff solid. MPt 112-114° C.; ¹H-NMR (CDCl₃) δ 1.2-1.85 (10H, m), 2.92(2H, t), 3.15 (2H, t), 4.17 (2H, s), 7.22 (1H, d), 7.42 (2H, m), 7.69(1H, d) and 7.8-8.0 (3H, m); MS (EI) M=461; C₂₂H₂₄ClN₃O₂S₂ requires 461.

Example 42 2-(6-Phenylhex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (4H, m), 1.6 (4H, m), 2.55 (2H, t), 3.07 (2H, t), 3.62 (2H, s),7.1-7.3 (5H, m), 7.63 (1H, m), 7.81 (1H, s), 8.39 (1H, m), 8.48 (1H, d).

Example 43 2-(7-Phenylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (6H, m), 1.6 (4H, m), 2.55 (2H, t), 3.07 (2H, t), 3.62 (2H, s),7.1-7.3 (5H, m), 7.63 (1H, m), 7.82 (1H, s), 8.39 (1H, m), 8.48 (1H, d).

Example 44 2-(8-Phenyloct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (8H, m), 1.6 (4H, m), 2.55 (2H, t), 2.97 (2H, t), 3.62 (2H, s),7.1-7.3 (5H, m), 7.63 (1), m), 7.82 (1H, s), 8.39 (1H, m), 8.48 (1H, d).

Example 45 2-(9-Phenylnon-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ1.3 (10H, m), 1.6 (4H, m), 2.55 (2H, t), 3.07 (2H, t), 3.62 (2H, s),7.1-7.3 (5H, m), 7.63 (1H, m), 7.81 (1H, s), 8.39 (1H, m), 8.48 (1H, d).

Example 462-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediates B19 and A27 by general method A5. ¹H-NMR(d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6 (2H, m), 3.08 (2H, t), 3.40(2H, t), 3.62 (2H, s), 4.43 (2H, s), 7.1-7.3 (5H, m), 7.64 (6H, m), 7.82(1H, s), 8.39 (1H, m), 8.49 (1H, d).

Example 472-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediates B19 and A1 by general method A1 as a whitesolid. MPt 105-107° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (6H, m), 1.6 (4H, m),3.00 (2H, t), 3.08 (2H, t), 3.62 (2H, s), 7.3 (1H, m), 7.58 (2H, d), 7.6(1H, m), 7.82 (1H, s), 7.97 (2H, d), 8.39 (1H, m), 8.48 (1H, m).

Example 482-(8-(4-Fluorophenyl)non-8-en-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediates B19 and A37 by general method A1 as a whitepowder. MPt 70-75° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.8 (10H, m), 2.45 (2H,t), 3.06 (2H, m), 3.62 (2H, s), 5.04 (1H, s), 5.26 (1H, s), 7.16 (2H,t), 7.29 (1H, dxd), 7.4-7.55 (2H, m), 7.81 (1H, s), 8.38 (1H, m) and8.48 (1H, d); MS (EI) Found M=437, C₂₅H₂₈FN₃OS requires 437.

Example 492-(6-(4-Chlorobenzoylamino)hex-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A45 by general method A1 as a whitesolid. MPt 135-139° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.8 (8H, m), 3.09 (2H,t), 3.23 (2H, q), 3.61 (2H, s), 7.28 (1H, s), 7.51 (2H, m), 7.62 (1H,m), 7.84 (3H, m), 8.38 (1H, m), 8.48 (1H, bs) and 8.53 (1H, bt).

Example 502-(8-(4-Bromophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A4 by general method A1 as a whitesolid. MPt 132-137° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H,m), 2.98 (2H, t), 3.08 (2H, t), 3.62 (2H, t), 7.28 (1H, m), 7.5-7.95(6H, m), 8.38 (1H, m) and 8.48 (1H, bd).

Example 512-(7-(4-Chlorophenoxy)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A29 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 3.09 (2H, t), 3.62 (2H, s),3.93 (2H, t), 6.94 (2H, m), 7.29 (2H, m), 7.63 (1H, m), 7.83 (1H, bs),8.38 (1H, m) and 8.48 (1H, bd).

Example 522-(7-Phenoxyhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A28 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 3.09 (2H, t), 3.62 (2H, s),3.93 (2H, t), 6.90 (3H, m), 7.27 (3H, m), 7.63 (1H, m), 7.82 (1H, s),8.39 (1H, m) and 8.48 (1H, m).

Example 532-(7-Phenylthiohept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A33 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 2.94 (2H, t), 3.06 (2H, t),3.62 (2H, s), 7.16 (1H, m), 7.20-7.35 (5H, m), 7.62 (1H, m), 7.81 (1H,s), 8.38 (1H, m) and 8.48 (1H, bs).

Example 542-(7-(4-Chlorophenylthio)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A30 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 2.94 (2H, t), 3.07 (2H, t),3.62 (2H, s), 7.2-7.5 (5H, m), 7.62 (1H, m), 7.82 (1H, s), 8.38 (1H, m)and 8.48 (1H, bs).

Example 552-(6-(3-Chlorophenyl)hex-1-yl)thio-5-(pyrid-3-ylmethylopyrimidin-4-one

Prepared from intermediate B19 and A40 by general method A1 as a whitesolid. MPt 84-85° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (8H, m), 2.57 (2H, t),3.13 (2H, t), 3.74 (2H, s), 7.03 (1H, m), 7.15-7.25 (4H, m), 7.65 (2H,m), 8.47 (1H, m),and 8.56 (1H, d); MS (EI) M=413; C₂₂H₂₄ClN₃OS requires413.

Example 562-(7-Phenylsulfinylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyzimidin-4-one

Prepared from intermediate B19 and A34 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 2.6-3.0 (4H, m), 3.55 (2H, s),7.25 (1H, m), 7.45-7.7 (7H, m), 8.35 (1H, m) and 8.46 (1H, m).

Example 572-(7-(4-Chlorophenylsulfinyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B19 and A31 by general method A1. ¹H-NMR (d6DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 2.7-3.2 (4H, m), 3.61 (2H, s),7.28 (1H, m), 7.55-7.75 (5H, m), 7.80 (1H, s), 8.38 (1H, m) and 8.47(1H, bs).

Example 582-(7-Phenylsulfonylhept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A35 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 3.05 (2H, t), 3.29 (2H, t),3.62 (2H, s), 7.29 (1H, m), 7.6-78.0 (7H, m), 8.44 (1H, m) and 8.49 (1H,m).

Example 592-(7-(4-Chlorophenylsulfonyl)hept-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A32 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 3.05 (2H, t), 3.62 (2H, s),7.28 (1H, m), 7.6-80 (6H, m), 8.44 (1H, m) and 8.48 (1H, m).

Example 602-(8-(3-Chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A18 by general method A1 as a whitesolid. MPt 68-70° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5 (8H, m), 1.5-1.8 (4H, m),2.56 (2H, t), 3.13 (2H, t), 3.74 (2H, t), 7.05 (1H, m), 7.15-7.25 (4H,m), 7.65 (2H, m), 8.46 (1H, m) and 8.57 (1H, m); MS (EI) M=441;C₂₄H₂₈ClN₃OS requires 441.

Example 612-(8-(3,4-Dichlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A 15 by general method A1 as a whitesolid. MPt 96-99° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5 (8H, m), 1.5-1.8 (4H, m),2.54 (2H, t), 3.13 (2H, t), 3.74 (2H, s), 7.0 (1H, m), 7.2-7.35 (3H, m),7.65 (2H, m), 8.46 (1H, m) and 8.56 (1H, d); MS (EI) M=475; C₂₄H₂₇Cl₂N₃Orequires 475.

Example 622-(8-(2-Thienyl)-8-oxooct-1-yl)thio-5-(pyrid-3ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A5 by general method A1 as a lightbrown solid. MPt 101-102° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.45 (6H, m),1.5-1.75 (4H, m), 2.79 (2H, t), 3.07 (2H, t), 3.61 (2H, s), 6.69 (1H,dd), 7.2-7.3 (1H, m), 7.45 (1H, d), 7.6-7.7 (1H, m), 7.81 (1H, s), 7.97(1H, s), 8.3-8.4 (1H, m) and 8.47 (1H, d).

Example 632-(8-(2-Furyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A6 by general method A1 as a lightbrown solid. MPt 104-107° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.45 (6H, m)1.5-1.8 (4H, m), 2.79 (2H, t), 3.07 (2H, t), 3.61 (2H, s), 6.69 (1H, m),7.28 (1H, m), 7.45 (1H, m), 7.63 (1H, m), 7.81 (1H, m), 7.97 (1H, m),8.38 (1H, m) and 8.48 (1H, m).

Example 642-(8-(2-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A 11 by general method A1 as a lightbrown solid. MPt 76-79° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5 (8H, m), 1.55-1.8(4H, m), 2.69 (2H, t), 3.07 (2H, t), 3.62 (2H, s), 7.05-7.4 (3H, m),7.55-7.75 (2H, m), 7.82 (1H, s) and 8.35-8.55 (3H, m).

Example 652-(9-(4-Chlorophenyl)-9-oxonon-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B19 and A1 by general method A1 as a whitesolid. MPt 112-114° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (14H), 2.92 (2H, t),3.11 (2H, t), 3.74 (2H, s), 7.2 (1H, m), 7.42 (2H, d), 7.6-7.75 (2H, m),7.88 (2H, m), 8.45 (1H, m) and 8.55 (1H, m); MS (EI) M=469;C₂₅H₂₈ClN₃O₂S requires 469.

Example 662-(8-(3,4-Dichlorophenyl)oct-7-yn-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B19 and A14 by general method A1 as a whitesolid. MPt 92-94° C.; ¹H-NMR (CDCl₃) δ 1.4-1.9 (8H, m), 2.39 (2H, t),3.15 (2H, t), 3.74 (2H, s), 7.1-7.4 (5H, m), 7.6-7.75 (2H, m), 8.45 (1H,m) and 8.57 (1H, m); MS (EI) M=471; C₂₄H₂₃Cl₂N₃OS requires 471.

Example 672-(8-(4-Acetylphenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A20 by general method A1 as a whitesolid. MPt 81-84° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8 (12H, m), 2.58 (3H, s),2.65 (2H, t), 3.13 (2H, t), 3.74 (2H, s), 7.1-7.35 (3H, m), 7.6-7.75(2H, m), 7.87 (2H, d) and 8.3-8.7 (2H, bd), MS (EI) M=449; C₂₆H₃₁N₃O₂Srequires 449.

Example 682-(8-(4-Methylnaphth-1-yl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B19 and A9 by general method A1 as a whitesolid. MPt 102-104° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H,m), 2.73 (3H, s), 3.02 (2H, t), 3.13 (2H, t), 3.73 (2H, s), 7.25 (1H,m), 7.28 (1H, d), 7.45-7.75 (4H, m), 7.75 (1H, d), 8.02 (1H, m), 8.45(1H, m) and 8.5-8.7 (2H, m); MS (EI) M=485; C₂₉H₃₁N₃O₂S requires 485.

Example 692-(8-(4-Pyridyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A23 by general method A1 as a whitesolid. MPt 86-88° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5 (8H, m), 1.5-1.8 (4H,m), 2.57 (2H, t), 3.07 (2H, t), 3.62 (2H, s), 7.21 (2H, d), 7.25 (1H,m), 7.81 (1H, s) and 8.3-8.6 (4H, m).

Example 702-(8-(4-Chlorophenyloct-1-yl)thio-5(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A24 by general method A1. ¹H-NMR (d₆DMSO) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H, m), 2.54 (2H, t), 3.07 (2H, t),3.61 (2H, s), 7.1-7.4 (5H, m), 7.63 (1H, m), 7.80 (1H, s), 8.38 (1H, m)and 8.47 (1H, bs).

Example 712-(4-(3-Phenylprop-1-yloxy)but-1-yl)thio-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B19 and A43 by general method A1. ¹H-NMR(d6-DMSO) δ 1.5-1.9 (6H, m), 2.59 (2H, t), 3.12 (2H, t), 3.3 (4H, m),3.61 (2H, s), 7.1-7.3(6H, m), 7.6 (1H, m), 7.81 (1H, s), 8.38 (1H, m),8.48 (1H, d).

Example 722-(6-Benzyloxyhex-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 and A27 by general method A1 as a lightbrown solid. MPt 120-122° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H,m), 1.6 (2H, m), 3.08 (2H, t), 3.39 (2H, t), 3.82 (2H, s), 4.42 (2H, s),7.3 (5H, m), 7.56 (1H, m), 7.70 (1H, m), 7.9-8.0 (3H, m), 8.13 (1H, d),8.85 (1H, d), 12.7 (1H, br s).

Example 732-(8-Phenyloct-1-yl)thio-5-(quinolin-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B16 by general method A1 as a light brownsolid. MPt 124-126° C.; ¹H-NMR (d₆-DMSO) δ 7.1-7.3 (5H, m), 7.56 (1H,m), 7.68 (1H, m), 7.9-8.0 (3H, m), 8.12 (1H, d), 8.85 (1H, d).

Example 742-(8-Phenyloct-1-yl)thio-5-((4-methoxypyrid-2-yl)methyl)pyrimidin-4-one

Prepared from intermediate B26 by general method B as a brown solidafter trituration with ether and recrystallisation from ethyl acetate.MPt 58-60° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.55 (2H,t), 3.07 (2H, t), 3.69 (2H, s), 3.78 (3H, s), 6.8 (2H, m), 7.1-7.3 (5H,m), 7.70 (1H, s), 8.25 (1H, d).

Example 752-(8-Phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one

A mixture of2-(8-phenyloct-1-yl)thio-5-(2-methoxypyrid-4-ylmethyl)pyrimidin-4-one(0.40 g, 0.9 mmol), chlorotrimethylsilane (0.23 ml, 1.8 mmol) and sodiumiodide (0.27 g, 1.8 mmol) in acetonitrile (30 ml) was heated at refluxfor 6 hours. The solvent was evaporated, the residue taken up indichloromethane, and washed with water and aqueous sodium thiosulphate.Evaporation of the solvent and trituration with ether gave2-(8-phenyloct-1-yl)thio-5-(2-oxopyrid-4-ylmethyl)pyrimidin-4-one as awhite solid (0.03 g). ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.55(2H, t), 3.07 (2H, t), 6.07 (2H, m), 7.1-7.3 (6H, m), 7.77 (1H, s); MPtindeterminate.

Example 76 2-(8-Phenyloct-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one

Prepared from intermediate B20 by general method A1 as a beige solid.MPt 124-125° C;, ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.55 (2H,t), 3.08 (2H, t), 3.63 (2H, s), 7.1-7.3 (7H, m), 7.83 (1H, s), 8.42 (2H,d).

Example 772-(6-Benzyloxyhex-1-yl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one

Prepared from intermediate B20 and A27 by general method A1 as a whitesolid. MPt 111-113° C.; ¹H-NMR (d₆-DMSO) δ 7.23 (2H, d), 7.3 (5H, m),7.83 (1H, s), 8.43 (2H, d), 1.28 (1H, br s).

Example 782-(8-(4-Chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B9 and A1 by general method A1 as a whitesolid. MPt 129-130° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5 (6H, m), 1.5-1.8 (4H,m), 2.93 (2H, t), 3.15 (2H, t), 3.71 (2H, s), 7.43 (2H, d), 7.78 (1H,s), 7.89 (2H, d), 8.72 (2H, s) and 9.07 (1H, s); MS (EI) M=456;C₂₃H₂₅ClN₄O₂S requires 456.

Example 79 2-(8-Phenyloct-1-yl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B13 by general method A1 as a light brownsolid. MPt 79-81° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (8H, m), 1.6 (4H, m), 2.55(2H, t), 3.07 (2H, t), 3.64 (2H, s), 6.08 (1H, m), 6.34 (1H, m), 7.1-7.3(5H, m), 7.51 (1H, m), 7.67 (1H, s).

Example 80 2-(6-Benzyloxyhex-1-yl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B13 and A27 by general method A1 as a brownsolid. MPt 63-65° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6(2H, m), 3.08 (2H, t), 3.40 (2H, t), 3.64 (2H, s), 4.43 (2H, s), 6.08(1H, m), 6.34 (1H, m), 7.3 (5H, m), 7.51 (1H, m), 7.68 (1H, s).

Example 81 2-(6Benzyloxyhex-1-yl)thio-5-(fur-3-ylmethyl)pyrimidin-4one

Prepared from intermediate B15 and A27 by general method A1 as a whitesolid. MPt 58-60° C.; ¹H-NMR (d₆-DMSO) δ 1.3 (4H, m), 1.5 (2H, m), 1.6(2H, m), 3.08 (2H, t), 3.4 (4H, m), 4.43 (2H, s), 6.37 (1H, m), 7.3 (5H,m), 7.44 (1H, m), 7.55 (1H, m), 7.68 (1H, s).

Example 82 2-(8-Phenyloct-1-yl)thio-5-(fur-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B15 by general method A1 as a white solid.MPt 78-80° C.; ¹H-NMR (d₆-DMSO) δ 6.37 (1H, s), 7.1-7.3 (5H, m), 7.44(1H, m), 7.55 (1H, m), 7.65 (1H, s).

Example 832-Benzylthio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B11 by general method A1 as a white solid.MPt 194-25 196° C.; ¹H-NMR (d₆-DMSO) δ 3.35 (3H, s), 3.44 (2H, s), 4.39(2H, s), 6.10 (1H, m), 6.16 (1H, s), 7.56 (1H, d), 7.86 (1H, s), 12.8(1H, br s).

Example 84 2-Benzylthio-5-(fur-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B13 by general method A5. ¹H-NMR (d₆-DMSO) δ0.366 (2H, s), 4.38 (2H, s), 6.09 (1H, m), 6.35 (1H, m), 7.2-7.4 (5H,m), 7.52 (1H, m), 7.74 ()1H, s).

Example 85 2-(3-Chlorobenzyl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B13 by general method A5. ¹H-NMR (d₆-DMSO) δ3.66 (2H, s), 4.39 (2H, s), 6.09 (1H, m), 6.35 (1H, m), 7.3-7.4 (5H, m),7.50 (1H, m), 7.74 (1H, s).

Example 86 2-(4-Chlorobenzyl)thio-5-(fur-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B13 by general method A5. ¹H-NMR (d₆-DMSO) δ3.63 (2H, s), 4.33 (2H, s), 6.07 (1H, m), 6.34 (1H, m), 7.35 (2H, d),7.42 (2H, d), 7.50 (1H, m), 7.64 (1H, s).

Example 87 2-Benzylthio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B121 by general method A1 as a white solid.MPt 226-228° C.; ¹H-NMR (d₆-DMSO) δ 2.40 (3H, s), 3.59 (2H, s), 4.38(2H, s), 7.14 (1H, d), 7.2-7.5 (5H, m), 7.52 (1H, dd), 7.84 (1H, s),8.34 (1H, d).

Example 88 2-Benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B25 by general method B as a white solid. MPt193-5° C.; ¹H-NMR (d₆-DMSO) δ 3.60 (2H, s), 3.81 (3H, s), 4.39 (2H, s),6.65 (1H, s), 6.85 (1, m), 7.25-7.42 (5H, m), 7.87 (1H, s), 8.03 (1H,m).

Example 89 2-Benzylthio-5-(pyrazin-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B14 by general method A1 as a white solid.MPt 174-175° C.; ¹H-NMR (d₆ DMS0) δ 3.84 (2H, s), 4.40 (2H, s), 7.1-7.5(5H, m), 7.89 (1H, bs), 8.47 (1H, d), 8.51 (1H, t) and 8.59 (1H, d); MS(FAB) M+1=311; C₁₆H₁₄N₄OS requires 310.

Example 90 2-Benzylthio-5-(thiazol-2-ylmethyl)pyrimidin-4-one

Prepared from intermediate B22 by general method A1 as light browncrystals; ¹H-NMR (d₆ DMSO) 4.02 (2H, s), 4.41 (2H, s), 7.2-7.45 (6H, m),7.55 (1H, d), 7.67 (1H, d) and 7.95 (1H, bs); MS (EI) M=315; C₁₅H₁₃N₃OS₂requires 315.

Example 91 2-(4-Chlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ3.59 (2H, s), 4.30 (2H, s), 7.26 (1H, m), 7.31 (2H, d), 7.41 (2H, d),7.63 (1H, m), 7.72 (1H, s), 8.37 (1H, m), 8.47 (1H, m).

Example 92 2-Benzylthio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ3.61 (2H, s), 4.33 (2H, s), 7.2-7.4 (5H, m), 7.64 (1H, m), 7.78 (1H, s),8.38 (1H, m), 8.49 (1H, m).

Example 932-(3,4-Dichlorobenzyl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from intermediate B19 by general method A5. ¹H-NMR (d₆-DMSO) δ3.60 (2H, s), 4.31 (2H, s), 7.26 (1H, m), 7.39 (1H, m), 7.53 (1H, d),7.65 (1H, m), 7.75 (1H, s), 8.37 (1H, m), 8.48 (1H, m).

Example 94 2-Benzylthio-5-(pyrid-4-ylmethyl)pyrimidin-4-one

Prepared from intermediate B20 by general method A1 as a white solid.MPt 183-185° C.; ¹H-NMR (d₆-DMSO) δ 3.64 (2H, s), 4.39 (2H, s), 7.24(2H, d), 7.3-7.4 (5H, m) 7.89 (1H, s), 8.43 (2H, d).

Example 95 2-(4-Chlorobenzyl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4-one

Prepared from intermediate B20 by general method A5. ¹H-NMR (d₆-DMSO) δ3.65 (2H, s), 4.38 (2H, s), 7.24 (2H, d), 7.37 (2H, d), 7.44 (2H, d),7.88 (1H, s), 8.43 (2H, d).

Example 96 2-(3,4-Dichlorobenzyl)thio-5-(pyrid-4-ylmethyl)pyrimidin-4one

Prepared from intermediate B20 by general method A5. ¹H-NMR (d₆-DMSO) δ3.66 (2H, s), 4.39 (2H, s), 7.25 (2H, d), 7.42 (1H, dd), 7.57 (1H, d),7.69 (1H, d), 7.89 (1H, s), 8.44 (2H, d).

Example 97 2-Benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B9 by general method A1 as a white solid. MPt239-241° C.; ¹H-NMR (d₆-DMSO) δ 3.65 (2H, s), 4.39 (2H, s), 7.1-7.5 (5H,m), 7.95 (1H, bs), 8.71 (2H, s) and 9.02 (1H, s); MS (EI) M=310;C₁₆H₁₄N₄OS requires 310.

Example 98 2-Benzylthio-5-(2-(pyrid-4-yl)ethyl)pyrimidin-4-one

Prepared from intermediate B17 by general method A1 as a white solid.MPt 209-2105° C.; ¹H-NMR (d₆-DMSO) δ 2.61 (2H, t), 2.81 (2H, t), 4.36(2H, s), 7.1-7.5 (7H, m), 7.69 (1H, s) and 8.45 (2H, d); MS (FAB)M+1=324; C₁₈H₁₇N₃OS requires 323.

Example 99 2-Benzylthio-5-benzylpyrimidin-4-one

Prepared from intermediate B23 by general method A1 as a brown solid.MPt 156-158° C.; ¹H-NMR (d₆-DMSO) δ 3.62 (2H, s), 4.38 (2H, s), 7.1-7.5(10H, m), 7.8 (1H, s), 12.8 (1H, br s).

Example 100 2-(8-Phenyloct-1-yl)oxy-5(pyrid-3-ylmethyl)pyrimidin-4-one

A mixture of 8-phenyl-1-octanol (1.5 g),2-nitroamino-5-(pyrid-3-ylmethyl)pyrimidin-4-one (1.0 g) and pyridine (5ml) was stirred at reflux for 24 hours, then the pyridine was removed byevaporation. Water was added, and the product extracted intodichloromethane, which was dried and evaporated. The residue waspurified by chromatography (silica, 0-5% methanol in dichloromethane)and recrystallisation from ether to give2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one as a palebuff solid (0.1 g). MPt 53-55° C.; ¹H-NMR (CDCl₃) δ 1.32 (8H, m), 1.60(2H, m), 1.74 (2H, m), 2.58 (2H, t), 3.72 (2H, t), 4.31 (2H, t), 7.1-7.3(6H, m), 7.54 (1H, m), 7.63 (1H, m), 8.45 (1H, m) and 8.55 (1H, d); MS(EI) Found M=391; C₂₄H₂₉N₃O₂ requires 391.

Example 1012-(8-(4-Chlorophenyl)-8-oxooct-1-yl)oxy-5-(pyrid-3-ylmethyl)-pyrimidin-4-one

Prepared from intermediates B24 and A2 analogously to example 100.Recrystallisation from acetonitrile/ether gave the product as anoff-white solid. MPt 116-7° C.; ¹H-NMR (CDCl₃) δ 1.39 (6H, m), 1.74 (4H,m), 2.93 (2H, t), 3.72 (2H, t), 4.31 (2H, t), 7.2 (1H, m), 7.42 (2H, d),7.55 (1H, s), 7.62 (1H, d), 7.88 (2H, d), 8.45 (1H, m) and 8.54 (1H, d);MS (FAB) M+1=440; C₂₄H₂₆ClN₃O₂ requires 439.

Example 1022-(4-Phenylbut-1-yl)oxy-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Finely ground cyanamide (1.68 g, 0.04 mol) and cyanamide dihydrochloride(2.26 g, 0.02 mol) were treated with 4-phenyl-1-butanol (3.24 g, 0.02mol), occasionally stirring with a glass rod over a 20 day period. Thewhite paste was dissolved in water, extracted with chloroform and theaqueous layer adjusted to pH 13 (conc. sodium hydroxide) with icecooling. The oil which precipitated was extracted into ethyl acetate,dried (MgSO₄) and the solvent evaporated to give the isourea as a clearoil (3.88 g). A portion of this material (2.44 g) was converted to thehydrochloride salt by treatment with HCl/ethanol/ether, the solventsevaporated and the residue washed several times with ether and driedunder high vacuum to yield 1.47 g.

This material (1.47 g, 0.00646 mol) was dissolved in ethanol (40 ml)together with ethyl 2-formyl-3-(6-methylpyrid-3-yl)propionate (0.95 g,0.00431 mol) and triethylamine and heated under reflux for 6 h. Thesolvent was evaporated and the residue treated with water and extractedwith ethyl acetate, dried (MgSO₄) and evaporated to an oil. Purificationby chromatography (silica, methanol/chloroform) followed bycrystallisation from ethyl acetate-petrol gave2-(4-phenylbut-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)-pyrimidin-4-one,yield 0.09 g (6%). MPt 88-90° C.; ¹H-NMR (CDCl₃) δ 1.75 (4H, m), 2.49(3H, s), 2.65 (2H, t), 3.64 (2H, s), 4.32 (2H, t), 6.90-7.60 (8H, m),8.38 (1H, m).

Example 1032-(2-Phenylethyl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B21 by general method B as white crystals,MPt 158-160° C. ¹H-NMR (d₆-DMSO) δ 2.41 (3H, s), 2.93 (2H, t), 3.3(2H+H₂O, t), 3.58 (2H, s), 7.14 (1H, d), 7.2-7.3 (5H, m), 7.52 (1H, dd),7.83 (1H, s), 8.34 (1H, d), 12.7 (1H, br s).

Example 1042-(2-Phenylethyl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B25 by general method B as white crystals;MPt 139-140° C. ¹H-NMR (d₆-DMSO) δ 2.94 (2H, t), 3.3 (2H+H₂O, t), 3.59(2H, s), 3.81 (3H, s), 6.65 (1H, s), 6.86 (1H, dd), 7.2-7.3 (5H, m),7.85 (1H, br s), 8.03 (1H, d)

Example 105 2-Benzylthio-5-((1-methyipyrazol-4-yl)methyl)pyrimidin-4one

Prepared from intermediate B34 by general method A1 as a whitecrystalline solid. ¹H-NMR (d₆-DMSO) δ 3.37 (2H, s), 3.71 (3H, s), 4.33(2H, s), 7.2-7.4 (6H, m), 7.41 (1H, s), 7.67 (1H, br s), 12.7 (1H, brs); (APCI) M+H=313. C₁₆H₁₆N₄OS requires 312.

Example 1062-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B9 by general method A4. ¹H-NMR (d₆-DMSO) δ3.65 (2H, s), 4.38 (2H, s), 7.05-7.2 (2H, m), 7.35-7.5 (2H, m), 7.94(1H, bs), 8.71 (2H, s), 9.06 (1H, s); MS (APCI−) found (M−1)=327;C₁₆H₁₃FN₄OS requires 328.

Example 1072-(3,4-Difluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B39 by general method A4. ¹H-NMR (d6-DMSO) δ3.57 (2H, s), 3.87 (3H, s), 4.37 (2H, s), 7.24-7.53 (3H, m), 7.88 (1H,br, s), 8.49 (2H, s), 12.88 (1H, br s); MS (APCI+) found (M+1)=377;C₁₇H₂₀F₂N₄O₂S requires 376.

Example 108 2-(4-Fluorobenzylthio)-5-((2-methoxypyrimid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B39 by general method A4. ¹H-NMR (d₆ DMSO) δ3.55 (2H, s), 3.85 (3H, s), 4.36 (2H, s), 7.0-7.2 (2H, m), 7.35-7.5 (2H,m), 7.86 (1H, bs), 8.48 (2H, s) 12.81 (1H, b); MS (APCI+) found(M+1)=359; C₁₇H₁₅FN₄O₂S requires 358.

Example 1092-(4-Fluorobenzylthio)-5-((2-benzyloxypyrimid-5-yl)methyl)pyrimidin-4-one

Prepared from intermediate B40 by general method A4. ¹H-NMR (d₆-DMSO) δ3.57 (2H, s), 4.38 (2H, s), 5.35 (2H, s), 7.0-7.2 (2H, m), 7.25-7.5 (7H,m), 7.87 (1H, bs), 8.51 (2H, s); MS (APCI+) found (M+1)=435;C₂₃H₁₉FN₄O₂S requires 434.

Example 1101-(4-Hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B46 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.1-2.3(18H, m), 2.94(2H, t), 3.24(2H, t), 3.6-3.8(3H, m), 4.2(1H, m), 7.12 (1H, s). 7.45(2H, m), 7.90(2H, m), 8.71(2H, s) and9.09(1H, s); MS (APCI+) found (M+1)=555; C₂₉H₃₅ClN₄O₃S requires 554.

Example 1111-(2-Methoxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from intermediate B87 by general method A4. ¹H-NMR (CDCl₃) δ1.25-1.85(10H, m), 2.93(2H, t), 3.26(2H, t), 3.32(3H, s), 3.62(2H, t),3.69(2H, s), 7.08(1H, s), 7.43(2H, m), 7.90(2H, m), 8.70(2H, s) and9.09(1H, s); MS (APCI+) found (M+1)=515; C₂₆H₃₁ClN₄O₃S requires 514.

Example 1121-(3-(1-Imidazolyl)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B47 and A1 by general method A4, as a yellowoil. ¹H-NMR (CDCl₃) δ 1.38 (6H, m), 1.70 (4H, m), 2.25 (2H, m), 2.91(2H, t), 3.25 (2H, t), 3.69 (2H, s), 3.77 (2H, t), 4.07 (2H, t), 6.81(1H, s), 6.92 (1H, s), 7 13 (1H, s), 7.43 (2H, d), 7.50 (1H, s), 7.89(2H, d), 8.70 (2H, s), 9.10 (1H, s); MS APCI+) found (M+1)=565;C₂₉H₃₃ClN₆O₂S requires 564.

Example 1131-(3-(1-Morpholino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B48 and A1 by general method A4, as a thickgum. ¹H-NMR (CDCl₃) δ 1.2-1.8(10H, m), 1.93(2H, m), 2.25-2.5(6H, m),2.93(2H, t), 3.25 (2H, t), 3.55-3.8(6H, m), 3.90(2H, t), 7.07(1H, s),7.45(2H, m), 7.90(2H, m), 8.72(2H, s) and 9.12(1H, s); MS (APCI+) found(M+1)=584, C₃₀H₃₈ClN₅O₃S requires 583.

Example 1141-(3-(2-Oxo-1-pyrrolidino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B49 and A1 by general method A4, as a yellowoil. ¹H-NMR (CDCl₃) δ 1.38 (6H, m), 1.74 (4H, m), 1.98 (2H, m), 2.10(2H, m), 2.43 (2H, t), 2.93 (2H, m), 3.25 (2H, t), 3.34 (2H, t), 3.41(2H, t), 3.70 (2H, s), 3.82 (2H, t), 7.43 (2H, m), 7.54 (1H, s), 7.89(2H, m), 8.74 (2H, s), 9.07 (1H, s); MS APCI+) found (M+1)=582;C₃₀H₃₆ClN₅O₃S requires 581.

Example 1151-(3-Dimethylaminoprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B51 and A1 by general method A4, as a thickgum. ¹H-NMR (CDCl₃) δ 1.2-1.8(10H, m), 1.8-2.05(4H, m), 2.14(3H, s),2.19(3H, s), 2.93(2H, t), 3.24(2H, t), 3.70(2H, s), 7.42(2H, m),7.88(2H, m) 8.72(2H, s) and 9.09(1H, s), MS (APCI+) found (M+1)=542;C₂₈H₃₆ClN₅O₂S requires 541.

Example 1161-(3-Hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B52 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.3-1.55 (6H, m), 1.6-1.85 (4H), 1.95-2.1(2H, m), 2.93(2H, t),3.25(2H, t), 3.6-3.8 (4H, m), 4.01(2H, t), 7.11(1H, s) 7.45(2H, d),7.89(2H, d), 8.70(2H, m) and 9.08(1H, s); MS (APCI+) found (M+1)=515;C₂₆H₃₁ClN₄O₃S requires 514.

Example 1171-(3-Hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediate B52and A24 by general method A4, as acolourless powder. MPt 76-77° C.; ¹H-NMR (CDCl₃) δ 1.2-2.0(14H, m),2.56(2H, t), 3.25(2H, t), 3.61(2H, t ), 3.73(2H, s), 3.88(2H, t),6.76(1H, s), 7.09(1H, d) and 7.15-7.4(7H, m), MS (FAB) found M+H=499;C₂₈H₃₅ClN₂O₂S requires 498.

Example 1181-(3-Methoxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B54 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.2-1.85(10H, m), 2.00(2H, m), 2.94(2H, t), 3.2-3.4(7H, m),3.70(2H, s), 3.92(2H, t), 6.99(1H, s), 7.44(2H, m), 7.90(2H, m),8.71(2H, s) and 9.10(1H, s); MS (APCI+) found (M+1)=529; C₂₇H₃₃ClN₄O₃Srequires 528.

Example 1191-(3-Phenylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B55 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.2-1.85(10H, m), 2.11(2H, quintet), 2.69(2H, t), 2.93(2H, t),3.24(2H, t), 3.67(2H, s), 3.78 (2H, t), 6.84(1H, s), 7.1-7.5(7H, m),7.90(2H, m), 8.70(2H, s) and 9.10(1H, s); MS (APCI+) found (M+1)=575;C₃₂H₃₅ClN₄O₂S requires 574.

Example 1201-(5-Hydroxypent-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B56 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.3-1.9(16H, m), 2.94(2H, t), 3.25(2H, t), 3.6-3.75(4H-m)3.80(2H, t), 6.96(1H, m), 7.44 (2H, m), 7.90(2H, m), 8.71(2H, s) and9.09(1H, s); MS (APCI+) found (M+1)=543; C₂₈H₃₅ClN₄O₃S requires 542.

Example 1211-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B45 and A1 by general method A4, as a whitesolid. ¹H-NMR (CDCl₃) δ 1.3-1.5 (6H, m), 1.6-1.8(4H, m), 2.92(2H, t),3.25(2H, t), 3.71(2H, s), 5.06(2H, s), 7.2-7.35(3H, m), 7.6-7.8(1H, m),8.5-8.6(1H, m), 8.70(2H, s), and 9.10(1H, s); MS (APCI+) found(M+1)=548; C₂₉H₃₀ClN₅O₂S requires 547.

Example 1221-(Pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediate B57 and A24 by general method A4, as a palebrown oil. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.85(4H, m), 2.55(2H,t), 3.24(2H, t), 3.77(2H, s), 5.00(2H, s), 6.88(1H, s), 7.09(2H, d),7.25-7.4(9H, m), 7.68(1H, m) and 8.57(1H, m); MS (EI) found M=531;C₃₁H₃₄ClN₃OS requires 531.

Example 1231-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B58 and A1 by general method A4, as a buffcoloured solid. MPt 105-106° C.; ¹H-NMR (CDCl₃) δ 1.36 (6H, m), 1.71(4H, m), 2.96 (2H, t), 3.26 (2H, t), 3.49 (3H, s), 3.53 (2H, s), 5.02(2H, s), 6.14 (1H, m), 6.34 (1H, s), 6.99 (1H, s), 7.17 (1H, m),7.25-7.55 (4H, m), 7.91 (2H, d), 8.52 (1H, s), 8.64 (1H, m); MS (APCI+)found (M+1)=577; C₃₁H₃₃ClN₄O₃S requires 576.

Example 1241-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B59 and A1 by general method A4, as a whitesolid. MPt 80-83° C.; ¹H-NMR (CDCl₃) δ 1.40 (6H, m), 1.69 (4H, m), 2.93(2H, t), 3.26 (2H, t), 3.69 (2H, s), 5.04 (2H, s), 7.04 (1H, s),7.30-7.56 (4H, m), 7.91 (2H, d), 8.55 (1H, m), 8.68 (3H, m), 9.10 (1H,s); MS (APCI+) found (M+1)=548; C₂₉H₃₀ClN₅O₂S requires 547.

Example 1251-(Pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediate B60 and A24 by general method A4, as a palebrown oil. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.85(4H, m), 2.56(2H,t), 3.26(2H, t), 3.75 (2H, s), 4.92(2H, s), 6.66(1H, s), 7.09(1H, d),7.15-7.5(9H, m), 8.45(1H, m) and 8.59(1H, m); MS (EI) found 531;C₃₁H₃₄ClN₃OS requires 531.

Example 1261-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4one

Prepared from intermediate B61 and A24 by general method A4, as anorange gum. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.75(4H, m), 2.55(2H,t), 3.24(2H, t), 3.49(3H, s), 3.55(2H, s), 5.01(2H, s), 6.16(1H, m),6.35(1H, bs), 6.9-7.35(8H, m) and 8.63(2H, m); MS (FAB) M+1=563;C₃₁H₃₅ClN₄O₂S requires 562.

Example 1271(Pyrid-4ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B61 and A1 by general method A4, as anoff-white solid. MPt 113-114° C.; ¹H-NMR (CDCl₃) δ 1.29 (6H, m), 1.63(4H, m), 2.86 (2H, t), 3.19 (2H, t), 3.43 (3H, s), 3.49 (2H, s), 4.95(2H, s), 6.09 (1H, m), 6.29 (1H, m), 6.89 (1H, s), 6.99 (2H, m), 7.12(1H, d), 7.36 (2H, d), 7.83 (2H, d), 8.58 (2H, m).

Example 1281-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin4-one

Prepared from intermediate B62 and A1 by general method A4, as a buffcoloured solid. MPt 75-77° C.; ¹H-NMR (CDCl₃) δ 1.35 (6H, m), 1.67 (4H,m), 2.92 (2H, t), 3.27 (2H, t), 3.72 (2H, s), 5.02 (2H, s), 6.99 (1H,s), 7.05 (2H, m), 7.43 (2H, d), 7.89 (2H, d), 8.64 (4H, m), 9.09 (1H,s); MS (APCI+) found (M+1)=548; C₂₉H₃₀ClN₅OS requires 547.

Example 1291-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediate B63 and A24 by general method A4, as a buffpowder. MPt 108-110° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m), 2.55(2H, t),3.25(2H, t), 3.77 (2H, s), 4.91(2H, s), 6.62(1H, s), 6.68(2H, d),7.08(2H, d), 7.15-7.4(7H, m) and 8.5-8.7(2H, m); MS (EI) found M=531;C₃₁H₃₄ClN₃OS requires 531.

Example 1301-(Pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thiopyrimidin-4-one

Prepared from intermediate B64 and A24 by general method A4, as a browngum. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.55(2H, t),3.24(2H, t), 5.04(2H, s), 6.11(1H, d), 7.0-7.4(7H, m) and 8.65(2H, m);MS (EI) M=441; C₂₄H₂₈ClN₃OS requires 441.

Example 1311-(2-(Pyrid-2-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B65 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.2-1.8(10H, m), 2.94(2H, t), 3.2-3.35(4H, m), 3.53(2H, s),4.32(2H, t), 6.74(1H, s), 7.04(1H, m), 7.20(1H, m), 7.43(2H, m),7.57(1H, m), 7.88(2H, m), 8.4-8.55(3H, m) and 9.09(1H, s); MS (APCI+)found (M+1)=562; C₃₀H₃₂ClN₅O₂S requires 561.

Example 1321-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B66 and A1 by general method A4, as a creamcoloured crystalline solid. MPt 121-123° C.; ¹H-NMR (CDCl₃) δ 1.42 (6H,m), 1.7 (4H, m), 2.94 (2H, t), 3.07 (2H, t), 3.29 (2H, t), 3.45 (2H, s),3.51 (3H, s), 4.01 (2H, t), 6.05 (1H, m), 6.28 (1H, m), 6.64 (1H, s),7.16 (1H, d), 7.26 (1H, m), 7.45 (3H, m), 7.89 (2H, d), 8.45 (1H, m),8.54 (1H, m); MS (APCI+) found (M+1)=591; C₃₂H₃₅ClN₄O₃S requires 590.

Example 1331-(2-(Pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B67 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.3-1.9 (10H, m), 2.94 (2H, t), 3.08 (2H, t), 3.58(2H, s),4.03(2H, t), 6.57 (1H, s), 7.43 (2H, m), 7.90 (2H, m), 8.44 (1H, m),8.55 (3H, m) and 9.09 (1H, m); MS (APCI+) found (M+1)=562; C₃₀H₃₂ClN₅O₂Srequires 561.

Example 1341-(2-(Pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B68 and A1 by general method A4, as a creamcoloured crystalline solid. MPt 129-130° C.; ¹H-NMR (CDCl₃) δ 1.40 (6H,m), 1.70 (4H, m), 2.95 (2H, t), 3.06 (2H, t), 3.30 (2H, t), 3.44 (2H,s), 3.51 (3H, s), 4.04 (2H, t), 5.95 (1H, m), 6.29 (1H, m), 6.56 (1H,s), 7.08 (2H, m), 7.17 (1H, d), 7.44 (2H, d), 7.90 (2H, d), 8.53 (2H,m); MS (APCI+) found (M+1)=591; C₃₂H₃₅ClN₄O₃S requires 590.

Example 1351-(2-(Pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B69 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.25-1.9(10H, m), 2.91(2H, t), 3.06(2H, t), 3.29(2H, t),3.59(2H, s), 4.04(2H, t), 6.62 (1H, s), 7.07(2H, m), 7.43(2H, m),7.90(2H, m), 8.45-8.7(4H, m) and 9.10(1H, s); MS (APCI+) found(M+1)=562; C₃₀H₃₂ClN₅O₂S requires 561.

Example 1361-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B70 and A24 by general method A4, as a palebrown gum. ¹H-NMR (d₆-DMSO) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.54(2H,t), 3.01(2H, t), 3.11(2H, t), 3.26(2H, s), 3.35(3H+HOD), 4.09(2H, t),5.94(1H, dd), 6.10(1H, d), 7.1-7.4(9H, m) and 7.54(2H, m).

Example 1371-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 70 by general method C1, as a brown/green gum.¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m), 2.56(2H, t), 3.01(2H, t), 3.26(2H, t),3.51(2H, t), 3.97(2H, t), 6.27(1H, s), 7.0-7.5(11H, m), 8.30(1H, m) and8.46(1H, m); MS (FAB) M+1=546; C₃₂H₃₆ClN₃OS requires 545.

Example 1381-(2-Methylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B88 and A1 by general method A4. ¹H-NMR(d₆-DMSO) δ 0.88 (6H, d), 1.2-1.4 (6H, m), 2.5-2.7 (4H, m), 2.08 (1H,m), 3.00 (2H, t), 3.11 (2H, t), 3.57 (2H, s), 3.69 (2H, d), 7.58 (2H,d), 7.82 (1H, s), 7.97 (2H, d), 8.70 (2H, s), 9.01 (1H, s); MS (APCI)M=513; C₂₇H₃₃ClN₄O₂S requires 513.

Example 1391-Phenylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Benzenesulfonyl chloride (41 mg) was added to a solution of2-(8-(4chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one(103 mg) in pyridine (0.5 ml), and the mixture stirred overnight.Evaporation of the pyridine followed by chromatography (silica, 0-2%methanol in dichloromethane) gave1-phenylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one(25 mg). ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.56(2H, t),2.92(2H, t), 3.87(2H, s), 7.08(2H, d), 7.15-7.8(7H, m), 7.95(2H, m),8.29(1H, s) and 8.35-8.7(2H, bm).

Example 1401-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B71 and A24 by general method A4, as ayellow/orange gum. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2,56(2H, t), 3.25(2H, t), 3.49(3H, s), 3.52(2H, s), 4.99(2H, s),6.16(1H, dd), 6.34(1H, m), 6.95(1H, s) and 7.0-7.5 (10H, m); MS (EI)M=561; C₃₂H₃₆ClN₃O₂S requires 561.

Example 1411-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B71 and A1 by general method A4, as a palebrown solid. ¹H-NMR (CDCl₃) δ 1.38 (6H, m), 1.73 (4H, m), 2.93 (2H, t),3.26 (2H, t), 3.49 (3H, s), 3.52 (2H, s), 4.99 (2H, s), 6.16 (1H, m),6.33 (1H, m), 6.96 (1H, s), 7.16 (3H, m), 727-7.45 (5H, m), 7.90 (2H,d).

Example 1421-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from Example 30 by general method C1, as a pale yellow gum.¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m), 2.5-2.65(5H, m), 3.25(2H, t), 3.68(2H,s), 4.95(2H, s), 6.78(1H, s), 7.0-7.6(11H, m) and 8.31 (1H, d); MS (EI)found M=546; C₃₂H₃₆ClN₃OS requires 546.

Example 1431-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methylpyrid-5-yl)methyl)pyrimidin-4-one

Prepared from Example 21 by general method C1, as a pale yellow oil.¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.53(3H, s), 2.59(2H,t), 3.24(2H, t), 3.68(2H, s), 4.95(2H, s), 6.78(1H, s), 7.0-7.5(11H, m),7.52(1H, m) and 8.31 (1H, bs); MS (FAB) M+1=512; C₃₂H₃₇N₃OS requires511.

Example 1441-Benzyl-2-(8-phenyloct-1-yl)thio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 37 by general method C1, as a thick gum.¹H-NMR(CDCl₃) δ 1.2-1.8(10H, m), 2.59(2H, t), 3.26(2H, t), 3.66(2H, s),3.91(3H, s), 4.95(2H, s), 6.56(1H, bs), 6.73(1H, m), 6.78(1H, s),7.05-7.45(10H, m) and 8.03(1H, m); MS (APCI+) Found (M+1)=528.C₃₂H₃₇N₃O₂S requires 527.

Example 1451-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 47 by general method C1, as a colourless oil.¹H-NMR (CDCl₃) δ 1.25-1.5(6H, m), 1.5-1.85(4H, m), 2.93(2H, t), 3.25(2H,t), 3.71(2H, s), 4.96(2H, s), 6.83(1H, s), 7.05-7.5(8H, m), 7.60(1H,txd), 7.88(2H, d) and 8.4-8.55(2H, m); MS (EI) found M=545;C₃₁H₃₇ClN₃O₂S requires 545.

Example 1471-(2-Thienylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B73 and A1 by general method A4, as a whitecrystalline solid. MPt 68-70° C.; ¹H-NMR (CDCl₃) δ 1.38 (6H, m), 1.69(4H, m), 2.93 (2H, t), 3.29 (2H, t), 3.67 (2H, s), 5.14 (2H, s), 7.04(3H, m), 7.37 (1H, m), 7.43 (2H, m), 7.90 (2H, m), 8.67 (2H, s), 9.01(1H, s); MS APCI+) found (M+1)=553, C₂₈H₂₉ClN₄O₂S₂ requires 552.

Example 1481-(2,2-Dimethylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B74 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 0.98(9H, s), 1.2-1.85(10H, m), 2.93(2H, t), 3.24(2H, t),3.65(2H, s), 3.70(2H, s), 6.89(1H, s), 7.43(2H, m), 7.90(2H, m),8.69(2H, s) and 9.09(1H, s); MS (APCI+) found (M+1)=527; C₂₈H₃₅ClN₄O₂Srequires 526.

Example 1491-(2-(1-Piperidino)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B75 and A1 by general method A4, as a yellowoil. ¹H-NMR (CDCl₃) δ 1.34-1.90 (16H, m), 2.30-2.55 (6H, m), 2.93 (2H,t), 3.25 (2H, t), 3.71 (2H, s), 4.40 (2H, m), 7.02 (1H, s), 7.42 (2H,m), 7.89 (2H, m), 8.70 (2H, s), 9.09 (1H, s); MS APCI+) found (M+1)=568;C₃₀H₃₈ClN₅O₂S requires 567.

Example 1501-(2-Hydroxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B77 and A1 by general method A4. ¹H-NMR(CDCl₃) δ 1.3-1.8(10H, m), 2.93(2H, t), 3.25(2H, t), 3.66(2H, s),3.99(4H, m), 7.20(1H, s), 7.43(2H, m), 7.89(2H, m), 8.68(2H, s) and9.05(1H, s); MS (APCI+) found (M+1)=501, C₂₅H₂₉ClN₄O₃S requires 500.

Example 1511-(2-Hydroxyethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediates B78 and A24 by general method A4, as acolourless gum. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2.54(2H, t), 3.21(2H, t), 3.64(2H, s), 3.8-4.15(4H, m), 5.23(1H, bs),6.97(1H, s), 7.08(2H, d) and 7.1-7.45(7H, m).

Example 1521-Ethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B89 and A1 by general method A4. ¹H-NMR(d₆-DMSO) δ 1.2-1.4 (9H, m), 2.5-2.7 (4H, m), 2.84 (2H, t), 3.11 (2H,t), 3.56 (2H, s), 3.89 (2H, q), 7.58 (2H, d), 7.85 (1H, s), 7.97 (2H,d), 8.70 (2H, s), 9.01 (1H, s); MS (APCI) M=485; C₂₅H₂₉ClN₄O₂S requires485.

Example 1531-(Fur-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B81 and A1 by general method A4, as a lightbrown oil. ¹H-NMR (CDCl₃) δ 1.38 (6H, m), 1.70 (4H, m), 2.93 (2H, t),3.27 (2H, t), 3.69 (2H, s), 4.94 (2H, s), 6.40 (2H, m), 7.06 (1H, s),7.44 (3H, m), 7.90 (2H, m), 8.68 (2H, s), 9.09 (1H, s); MS APCI+) found(M+1)=537; C₂₈H₂₉ClN₄O₃S requires 536.

Example 1541-(Fur-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediates B82 and A24 by general method A4, as a palebrown gum. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.56(2H, t),3.27(2H, t), 3.73(2H, t), 4.85(2H, s), 6.33(2H, s), 6.73(1H, s),7.09(2H, d) and 7.2-7.5(8H, m); MS (FAB) M+1=521; C₃₀H₃₃ClN₂O₂S requires520.

Example 1551-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-one

1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one wasprepared from 1-methyl-2-thiouracil by general method A4. A solution ofbromine (0.05 ml) in dichloromethane (1 ml) was added to a slurry of1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one (0.38g) in dichloromethane (20 ml), and the mixture was stirred for 24 hours.The solution was washed with aqueous sodium carbonate, dried andevaporated. Chromatography (silica, 1-4% methanol in dichloromethane)gave1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-one(0.18 g), as a white solid. ¹H-NMR (CDCl₃) δ 1.3-1.5 (6H, m), 1.65-1.8(4H, m), 2.94 (2H, t), 3.26(2H, t), 3.56(3H, s), 7.45(2H, d), 7.56(1H,s) and 7.90(2H, d); MS (APCI+) found (M+1)=459; C₁₉H₂₂BrClN₂O₂S requires458.

Example 1561-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B83 and A24 by general method A4, as acolourless solid. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2.56(2H, t), 3.25(2H, t), 3.49(3H, s), 3.51(3H, s), 3.54(2H, s),6.19(1H, m), 6.38(1H, m), 6.93(1H, s) and 7.0-7.35(5H, m); MS (EI)M=485; C₂₆H₃₂ClN₃O₂S requires 485.

Example 1571-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B83 and A1 by general method A4, as a creamcoloured crystalline solid. MPt 90-5° C.; ¹H-NMR (CDCl₃) δ 1.38 (6H, m),1.72 (4H, m), 2.91 (2H, t), 3.26 (2H, t), 3.49 (3H, s), 3.51 (3H, s),3.54 (2H, s), 6.19 (1H, m), 6.38 (1H, s), 6.93 (1H, s), 7.19 (1H, m),7.43 (2H, d), 7.90 (2H, d); MS (APCI+) Found (M+1)=500; C₂₆H₃₀N₃O₃Srequires 499.

Example 1581-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 70 by general method C1, as a pale yellow oil.¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m), 2.56(2H, t), 3.22(2H, t), 3.46(3H, s),3.74(2H, s), 6.77(1H, s), 7.08(2H, d), 7.15-7.35(4H, m), 7.66(1H, txd)and 8.49(2H, bs); MS (EI) found M=455; C₂₅H₃₀ClN₃OS requires 455.

Example 1591-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B84 and A1 by general method A4, as a whitesolid. ¹H-NMR (CDCl₃) δ 1.3-1.55(6H, m), 1.6-1.85(4H, m), 2.93(2H, t),3.26(2H, t), 3.51(3H, s), 3.70(2H, s), 6.94(1H, s), 7.45(2H, d),7.89(2H, d), 8.70(2H, s) and 9.1(1H, s); MS (APCI+) found (M+1)=471;C₂₄H₂₇ClN₄O₂S requires 470.

Example 1601-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one

Prepared from intermediates B85 and A24 by general method A4, as acolourless powder. MPt 92-93° C.; ¹H-NMR (CDCl₃) δ 1.2-1.8(12H, m),2.56(2H, t), 3.26(2H, t), 3.40(3H, s), 3.76(2H, s), 6.59(1H, s),7.09(2H, d) and 7.15-7.45(7H, m); MS (EI) found M=454; C₂₆H₃₁ClN₂OSrequires 454.

Example 1611-Phenyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediates B86 and A24 by general method A4, as ayellow/orange solid. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2.54(2H, t), 3.14(2H, t), 3.49(3H, s), 3.57(2H, s), 6.22(1H, m),6.38(1H, m), 7.00(1H, s), 7.08(2H, d), 7.15-7.4(5H, m) and 7.5-7.6(3H,m); MS (EI) M=547; C₃₁H₃₄ClN₃O₂S requires 547.

Example 1621-Methylsulfonyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 70, analogously to example 139. ¹H-NMR (CDCl₃) δ1.2-1.8(12H, m), 2.56(2H, t), 3.10(2H, t), 3.55(3H, s), 4.03(2H, s),7.09(2H, m), 7.15-7.3(2H, m), 7.61(1H, m), 7.96(1H, m), 8.45(1H, s) and8.60(2H, m).

Example 1631-Benzyl-2-(8-phenyloct-1-yl)oxy-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 100 by general method C1, as a pale buff solid.MPt 74-78° C.; ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.85(4H, m),2.58(2H, t), 3.72(2H, s), 4.40(2H, t), 4.83(2H, s), 6.76(1H, s),7.0-7.4(11H, m), 7.6-7.7(1H, m) and 8.46(2H, m); IR 1655, 1621 cm−1.

Example 1641-(2-Methoxyethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B87 by general method A4. ¹H-NMR (CDCl₃) δ3.31(3H, s), 3.59(2H, t), 3.71(2H, s), 4.51(2H, s), 7.10(1H, s),7.2-7.45(5H, m), 8.72(2H, s) and 9.10(1H, s); MS (APCI+) found(M+1)=369; C₁₉H₂₀N₄O₂S requires 368.

Example 1651-(3-Phenylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B55 by general method A4. ¹H-NMR (CDCl₃) δ2.08(2H, quintet), 2.65(2H, t), 3.68(2H, s), 3.75(2H, t), 4.49(2H, s),5.30(2H, s), 6.48(1H, s), 7.10(2H, m), 7.15-7.5(8H, m), 8.69(2H, s) and9.10(1H, s); MS (APCI+) found (M+1)=429; C₂₅H₂₄N₄OS requires 428.

Example 1661-(5-Hydroxypent-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B56 by general method A4. ¹H-NMR (CDCl₃) δ1.3-1.9(6H, m), 3.64(2H, t), 3.7-3.9(4H, m), 4.50(2H, s), 6.98(1H, m),7.2-7.5(5H, m), 8.72(2H, s) and 9.10(1H, s); MS (APCI+) found (M+1)=397;C₂₁H₂₄N₄O₂S requires 396.

Example 1671-(Pyrid-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B45 by general method A4. ¹H-NMR (CDCl₃) δ3.73(2H, s), 4.49(2H, s), 5.03(2H, s), 7.1-7.4(8H, m), 7.69(1H, m),8.57(1H, m), 8.71(2H, s) and 9.09(1H, s); MS (APCI+) found (M+1)=402;C₂₂H₁₉N₅OS requires 401.

Example 1681-(Pyrid-3-ylmethyl)-2-benzylthio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B58 by general method A4, as a buff colouredsolid. ¹H-NMR (CDCl₃) δ 3.5 (3H, s), 3.55 (2H, s), 4.51 (2H, s), 4.99(2H, s), 6.27 (1H, s), 7.01 (1H, s), 7.15-7.50 (8H, m), 8.50 (1H, s),8.62 (1H, m); MS (APCI+) found (M+1)=431; C₂₄H₂₂N₄O₂S requires 430.

Example 169 1-(Pyrid-4-ylmethyl)-2-benzylthio-5-benzylpyrimidin-4-one

Prepared from intermediate B63 by general method A4, as a brown gum.¹H-NMR (CDCl₃) δ 3.78(2H, s), 4.50(2H, s), 4.89(2H, s), 6.64(1H, s),6.94(2H, d), 7.1-7.5(10H, m) and 8.58(2H, d); MS (EI) found M=399;C₂₄H₂₁N₃OS requires 399.

Example 1701-(2-(Pyrid-2-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B65 by general method A4. ¹H-NMR (CDCl₃) δ3.20(2H, t), 3.55(2H, s), 4.30(2H, t), 4.53(2H, s), 6.75(1H, s),6.96(1H, m), 7.17(1H, m), 7.25-7.5(5H, m), 7.56(1H, m), 8.4-8.55(3H, m)and 9.10(1H, s),; MS (APCI+) found (M+1)=416; C₂₃H₂₁N₅OS requires 415.

Example 1711-(2-(Pyrid-3-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B67 by general method A4. ¹H-NMR (CDCl₃) δ3.05(2H, t), 3.60(2H, s), 4.00(2H, t), 4.54(2H, s), 6.57(1H, s),7.1-7.5(6H, m), 8.43(1H, m), 8.5-8.65(3H, m) and 9.10(1H, s); MS (APCI+)found (M+1)=416; C₂₃H₂₁N₅OS requires 415.

Example 172 1-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-5ylmethyl)pyrimidin-4-one

Prepared from intermediate B68 by general method A4, as a buff colouredsolid. ¹H-NMR (CDCl₃) δ 3.02 (2H, t), 3.45 (2H, s), 3.52 (3H, s), 4.00(2H, t), 4.55 (2H, s), 5.95 (1H, m), 6.30 (1H, s), 6.57 (1H, s), 7.02(2H, m), 7.18 (1H, m), 7.19-7.44 (5H, m), 8.50 (2H, m); MS (APCI+) Found(M+1)=445; C₂₅H₂₄N₄O₂S requires 444.

Example 1731-(2-(Pyrid-4-yl)ethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B69 by general method A4. ¹H-NMR (CDCl3) δ3.03(2H, t), 3.60(2H, s), 4.01(2H, t), 4.54(2H, s), 6.61(1H, s),7.01(2H, m), 7.25-7.5(5H, m), 8.45-8.65(4H, m) and 9.11(1H, s); MS(APCI+) found (M+1)=416; C23H21N5OS requires 415.

Example 1741-(2-Phenylethyl)-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 88 by general method C1. ¹H-NMR (CDCl₃) δ 3.01(2H,t), 3.57(2H, s), 3.95(5H, m), 4.53(2H, m), 6.27(1H, s), 6.45(1H, s),6.55(1H, m), 7.02(2H, m ), 7.1-7.5(8H, m) and 8.02(1H, d); MS (APCI+)found M+H=444; C₂₆H₂₅N₃O₂S requires 443.

Example 1751-Benzyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate Example 88 by general method C1, as acolourless stiff gum. ¹H-NMR (CDCl₃) δ 3.67(2H, s), 3.90(3H, s),4.51(2H, s), 4.93(2H, s), 6.57(1H, s), 6.73(1H, m), 6.81(1H, s),7.10(1H, m), 7.25-7.45(9H, m) and 8.04(1H, d); MS (EI) M=429;C₂₅H₂₃N₃O₂S requires 429.

Example 1761-(2-Thienylmethyl)-2-benzylthio-5-(pyrimid-1-ylmethyl)pyrimidin-4one

Prepared from intermediate B73 by general method A4, as a pale yellowcrystalline solid. MPt 110-112° C.; ¹H-NMR (CDCl₃) δ 3.69 (2H, s), 4.54(2H, s), 5.11 (2H, s), 7.02 (3H, m), 7.30-7.42 (6H, m), 8.65 (2H, s),9.09 (1H, s); MS APCI+) found (M+1)=407; C₂₁H₁₈N₄OS₂ requires 406.

Example 1771-(2,2-Dimethylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B74 by general method A4. ¹H-NMR (CDCl₃) δ0.96(9H, s), 3.62(2H, s), 3.72(2H, s), 4.49(2H, s), 6.91(1H, s),7.25-7.45(5H, m), 8.70(2H, s) and 9.11(1H, s); MS (APCI+) found(M+1)=381; C₂₁H₂₄N₄OS requires 380.

Example 1781-(Fur-2-ylmethyl)-2benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4, as a brown oil.¹H-NMR (CDCl₃) δ 3.70 (2H, s), 4.52 (2H, s), 4.91 (2H, s), 6.40 (2H, m),7.06 (1H, s), 7.26-7.42 (6H, m), 8.70 (2H, s), 9.10 (1H, s); MS APCI+)found (M+1)=391; C₂₁H₁₈N₄O₂S requires 390.

Example 1791-Methyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 88 by general method C1, as a pale cream powder.MPt 119-120° C.; ¹H-NMR (CDCl₃) δ 3.44(3H, s), 3.69(2H, s), 3.93(3H, s),4.52(2H, s), 6.62(1H, bs), 6.78(2H, m), 7.2-7.5(5H, m) and 8.10(1H, m);MS (EI) M=353; C₁₉H₁₉N₃O₂S requires 353.

Example 1801-Benzyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B94 by general method A4. ¹H-NMR (CDCl₃) δ1.2-1.8 (12H, m), 2.55(2H, t), 3.25 (2H, t), 3.67 (2H, s), 5.00 (2H, s),6.8-7.4 (10H, m), 8.7 (2H, s), 9.07 (1H, s); (APCI) M+H=533.C₃₀H₃₃ClN₄OS requires 532.

Example 1811-(2-Phenylethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A4, as a whitecrystalline solid. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2.56(2H, t), 3.05 (2H, t), 3.29 (2H, t), 3.50(2H, s), 4.02 (2H, t),6.36(1H, s), 7.0-7.1 (4H, m), 7.2-7.3 (5H, m), 8.47(2H, s) and 9.07(1H,s); (APCI) M+H=547. C₃₁H₃₅ClN₄OS requires 546.

Example 1821-Methyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B84 by general method A4 as a whitecrystalline solid. ¹H-NMR (CDCl₃) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m),2.56(2H, t), 3.25 (2H, t), 3.50 (3H, st), 3.70(2H, s), 6.94(1H, s), 7.09(2H, m), 7.23 (2H, m), 8.69(2H, s) and 9.09(1H, s); (APCI) M+H=457.C₂₄H₂₉ClN₄OS requires 456.

Example 1831-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrid-4-yl)pyrimidin-4-one

1-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-pyrimidin-4-one wasprepared from 1-benzyl-2-thiouracil and intermediate A1 by generalmethod A4, then iodinated with iodine (1.2 equiv) and silvertrifluoromethanesulfonate (1 equiv) in chloroform at room temperatureovernight, giving1-benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-iodopyrimidin-4-onein 27% yield after chromatography. This compound (1 equiv) and4-pyridylboronic acid (2 equiv) were suspended in dimethoxyethane, 2Maqueous sodium carbonate added, followed bytetrakis(triphenylphosphine)palladium (0.05 equiv). The mixture wasrefluxed for 16 hours, then the solvent evaporated. Aqueous workup,chromatography and crystallisation from ether gave the title compound asa white crystalline solid. ¹H-NMR (CDCl₃) δ 1.3-1.5 (6H, m), 1.6-1.8(4H, m), 2.94 (2H, t), 3.32 (2H, t), 5.13 (2H, s), 7.27 (2H, d), 7.4(6H, m), 7.55 (2H, d), 7.90 (2H, d); (APCI) M+H=532. C₃₀H₃₀ClN₃O₂Srequires 531.

Example 1841-Benzyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B94 by general method A4. ¹H-NMR (CDCl₃) δ1.3-1.5 (4H, m), 1.6-1.8 (4H, m)2.93 (2H, t), 3.26 (2H, t), 3.67 (2H,s), 5.01 (2H, s), 6.98 (1H, s), 7.1-7.2 (2H, m), 7.4-7.5 (5H, m), 7.90(2H, d), 8.7 (2H, s), 9.07 (1H, s); (APCI) M+H=547. C₃₀H₃₁ClN₄O₂Srequires 546.

Example 1851-(2-Phenylethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A4 as a cream colouredcrystalline solid. ¹H-NMR (CDCl₃) δ 1.3-1.5(6H, m), 1.6-1.8(4H, m),2.94(2H, t), 3.05 (2H, t), 3.30 (2H, t), 3.50(2H, s), 4.03 (2H, t),6.37(1H, s), 7.05 (2H, m), 7.3 (3H, m), 7.43 (2H, d), 7.89 (2H, d), 8.47(2H, s), 9.08 (1H, s); (APCI) M+H=561. C₃₁H₃₃ClN₄O₂S requires 560.

Example 1861-(Fur-2-ylmethyl)-2-(2-phenylethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4. ¹H-NMR (CDCl₃) δ3.02 (2H, t), 3.54 (2H, t), 3.69 (2H, s), 4.91 (2H, s), 6.38 (2H, m),7.06 (1H, s), 7.2-7.35 (5H, m), 7.4 (1H, m), 8.7 (2H, s), 9.09 (1H, s);(APCI) M+H=405. C₂₂H₂₀N₄O₂S requires 404.

Example 1871-(2-Fluorobenzyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from intermediate B131 by general method A4. ¹H-NMR (CDCl₃) δ3.70 (2H, s), 4.51 (2H, s), 5.01 (2H, s), 7.08 (1H, s), 7.1-7.2 (3H, m),7.2-7.4 (6H, m), 8.7 (2H, s), 9.09 (1H, s), (APCI) M+H=419. C₂₃H₁₉FN₄OSrequires 418.

Example 1881-(8-Phenloctyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B90 by general method A4. ¹H-NMR (CDCl₃) δ1.2-1.4(8H, m), 1.5-1.8(4H, m), 2.59(2H, t), 3.6-3.8(4H, m), 4.50(2H,s), 6.93(1H, s), 7.1-7.5(10H, m), 8.70(2H, s) and 9.10(1H, s); (APCI)M+H=499. C₃₀H₃₄N₄OS requires 498.

Example 189 (9-Phenylnonyl)-2-benzylthio-5-(pyrimid-5-ylmethylpyrimidin-4-one

Prepared from intermediate B91 by general method A4 as a thick oil.¹H-NMR (CDCl₃) δ 1.2-1.4(10H, m), 1.5-1.85(4H, m), 2.59(2H, t),3.6-3.8(4H, m), 4.50(2H, s), 6.94(1H, s), 7.1-7.45(1H, m), 8.69(2H, s)and 9.10(1H, s); (APCI) M+H=513. C₃₁H₃₆N₄OS requires 512.

Example 190 1-Benzyl-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B94 by general method A4. ¹H-NMR (CDCl₃) δ3.68 (2H, s), 4.51 (2H, s), 4.97 (2H, s), 7.00 (1H, s), 7.1 (2H, m),7.2-7.4 (2H, m), 8.7(2H, s) and 9.08(1H, s); (APCI) M+H=401. C₂₃H₂₀N₄OSrequires 400.

Example 1911-Benzyl-2-benzylthio-5-((1-methylpyrazol-4-yl)methyl)pyrimidin-4-one

Prepared from Example 105 by general method C3, as a pale brown oil.¹H-NMR (CDCl₃) δ 3.57 (2H, s), 3.84 (3H, s), 4.52 (2H, s), 4.93 (2H, s),6.90 (1H, s), 7.1 (2H, s), 7.2-7.4 (10H, m); (APCI) M+H=403. C₂₃H₂₂N₄OSrequires 402.

Example 1921-Benzyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B94 by general method A4. ¹H-NMR (CDCl₃) δ3.68 (2H, s), 4.48 (2H, s), 4.97 (2H, s), 7.0 (3H, m), 7.1 (2H, m),7.3-7.4 (5H, m), 8.7 (2H, s), 9.08 (1H, s); (APCI) M+H=419. C₂₃H₁₉FN₄OSrequires 418.

Example 1931-(2,2-Dimethylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B74 by general method A4 as a oil. ¹H-NMR(CDCl₃) δ 0.96(9H, s), 3.61(2H, s), 3.72(2H, s), 4.46(2H, s),6.85-7.1(3H, m), 7.3-7.45(2H, m), 8.70(2H, s) and 9.11(1H, s); (APCI)M+H=399. C₂₁H₂₃FN₄OS requires 398.

Example 1941-(2-Phenylethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93, by general method A4, as a creamcoloured crystalline solid. ¹H-NMR (CDCl₃) δ 3.02 (2H, t), 3.51 (2H, s),4.00 (2H, t), 4.55 (2H, s), 6.37 (1H, s), 7.0 (2H, m), 7.2-7.4 (8H, m),8.47 (2H, s), 9.09 (1H, s); (APCI) M+H=415. C₂₄H₂₂N₄OS requires 414.

Example 1951-(Fur-2-ylmethyl)-2-(4-methylbenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4. ¹H-NMR (CDCl₃) δ2.33 (3H, s), 3.70 (2H, s), 4.49 (2H, s), 4.90 (2H, s), 6.3-6.4 (2H, m),6.84 (1H, s), 7.08 (2H, d), 7.33 (2H, d), 7.41 (1H, m), 8.7 (2H, s),9.10 (1H, s); (APCI) M+H=405. C₂₂H₂₀N₄OS requires 404.

Example 1961-(Fur-2-ylmethyl)-2-(2-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A4. ¹H-NMR (CDCl₃) δ3.70 (2H, s), 4.56 (2H, s), 4.90 (2H, s), 6.37 (1H, m), 6.41 (1H-m), 7.1(3H, m), 7.3 (1H, m), 7.41 (1, H, m), 7.55 (1H, m), 8.7 (2H, s), 9.10(1H, s); (APCI) M+H=409. C₂₁H₁₇FN₄O₂S requires 408.

Example 1971-(Fur-2-ylmethyl)-2-(4-chlorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4. ¹H-NMR (CDCl₃) δ3.69 (2H, s), 4.48 (2H, s), 4.90 (2H, s), 6.38 (2H, m), 7.06 (1H, m),7.28 (2H, d), 7.35 (2H, d), 7.42 (1H, m), 8.7 (2H, s), 9.10 (1H, s);(APCI) M+H=425, 2M+H=849. C₂₁H₁₇ClN₄O₂S requires 424.

Example 1981-(Fur-2-ylmethyl)-2-(3-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4. ¹H-NMR (CDCl₃) δ3.70 (2H, s), 4.51 (2H, s), 4.90 (2H, s), 6.38 (1H, m), 6.41 (1H, m),7.0 (1H, m), 7.1-7.3 (5H, m), 7.42 (1H, m), 8.7 (2H, s), 9.10 (1H, s);(APCI) M+H=409. C₂₁H₁₇FN₄O₂S requires 408.

Example 1991-(Fur-2-ylmethyl)-2-(3-chlorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B81 by general method A4, as an orange oil.¹H-NMR (CDCl₃) δ 3.69 (2H, s), 4.47(2H, s), 4.93 (2H, s), 6.38 (1H, m),6.41 (1H, m), 7.12 (1H, s), 7.2-7.4 (5H, m), 8.7 (2H, s), 9.08 (1H, s);(APCI) M+H=425. C₂₁H₁₇ClN₄O₂S requires 424.

Example 200 1-Methyl-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B84 by general method A4, as an off-whitecrystalline solid. ¹H-NMR (CDCl₃) δ 3.49 (3H, s), 3.71 (2H, s), 4.51(2H, s), 6.96 (1H, s), 7.2-7.5 (5H, m), 8.70 (2H, s), 9.10 (1H, s);(APCI) M+H=325. C₁₇H₁₆N₄OS requires 324.

Example 2011-((R)-Tetrahydofuran-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B133 by general method A4. White solid.¹H-NMR (CDCl₃) δ 1.37-1.60 (1H, m), 1.81-2.14 (3H, m), 3.53-3.87 (5H,m), 3.99-4.18 (2H, m), 4.50 (1H, s), 7.18(1H, s), 7.28-7.44 (5H, m),8.72 (2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=395 C₂₁H₂₂N₄O₂Srequires 394.

Example 2021-((S)-Tetrahydofuran-2-ylmethyl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B132 by general method A4, as a white solid.¹H-NMR (CDCl₃) δ 1.37-1.58 (1H, m), 1.8-2.12 (3H, m), 3.55-3.88 (5H, m),3.98-4.19 (2H, m), 4.5 (2H, s), 7.17 (1H, s), 7.29-7.44 (5H, m), 8.70(2H, s), 9.02(1H, s); MS (APCI⁺) found (M+1)=395; C₂₁H₂₂N₄O₂S requires394.

Example 2031-(4-Fluorobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B99 by general method A2, as an orange solid.¹H-NMR (CDCl₃) δ 3.68 (2H, s), 4.47 (2H, s), 4.94 (2H, s), 6.92-7.20(7H, m), 7.28-7.41 (2H, m), 8.66 (2H, s), 9.08 (1H, s); MS (APCI⁺) found(M+1)=437; C₂₃H₁₈F₂N₄OS requires 436.

Example 2041-(4-Bromobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B115 by general method A2. ¹H-NMR (CDCl₃) δ3.68 (2H, s), 4.46 (2H, s), 4.91 (2H, s), 7.01 (5H, m), 7.35 (2H, m),7.50 (2H, m), 8.70 (2H, s), 9.09 (1H, s), MS(APCI⁺) M+1=497,C₂₃H₁₈BrFN₄OS requires 496. MPt 162.2° C. (cream solid). MPt. 162.2

Example 2051-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B109 by general method A2 as an oil. ¹H-NMR(CDCl₃) δ 1.15-1.72 (8H, m), 2.50-2.63 (2H, t), 3.28-3.30 (2H, t),3.55-3.64 (2H, t), 3.69 (2H, ), 3.89-3.98 (2H, t), 4.47(2H, s),6.88-7.43 (9H, m), 8.69 (2H, s), 9.08 (1H, s); MS (APCI⁺) found(M+1)=551; C₃₀H₃₂F₂N₄O₂S requires 550.

Example 2061-(2-Phenoxyethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-)pyrimidin-4-one

Prepared from intermediate B101 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 3.72 (2H, s), 4.10-4.29 (4H, m), 4.47 (2H, s), 6.70-6.80 (2H,d), 6.95-7.39 (7H, m), 8.70 (2H, s), 9.12 (1H, s); MS (ES+) found(M+1)=467; C₂₄H₂₀F₂N₄O₂S requires 466.

Example 2071-(3-(5-Phenylpent-1-yloxy)prop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B139 by general method A2. ¹H-NMR (CDCl₃) δ1.35 (2H, m), 1.59 (4H, m), 1.95 (2H, m), 2.60 (2H, t), 3.32 (4H, m),3.68 (2H, s), 3.87 (2H, t), 4.50 (2H, s), 7.01 (1H, s), 7.14-7.38 (10H,m), 8.68(2H, s) 9.08 (1H, s); MS (APCI⁺) found (M+1)=515; C₃₀H₃₄N₄O₂Srequires 514.

Example 2081-(9-Phenylnonyl)-2-furfurylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B91 by general method A2. ¹H-NMR (CDCl₃) δ1.28 (10H, m), 1.65 (4H, m), 2.60 (2H, t), 3.69 (4H, m), 4.56 (2H, s),6.30 (1H, m), 6.40 (1H, m), 6.98 (1H, s), 7.14-7.36 (6H, m), 8.69 (2H,s), 9.10 (1H, s); MS (APCI⁺) found (M+1)=503; C₂₉H₃₄N₄O₂S requires 502.

Example 2091-(9-Phenylnonyl)-2-(thiazol-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B91 by general method A2. ¹H-NMR (CDCl₃) δ1.28 (10H, m), 1.65 (4H, m), 2.60 (2H, t), 3.72 (2H, s), 3.75 (2H, t),4.85 (2H, s), 6.97 (1H, s), 7.14-7.30 (6H, m), 7.71 (1H, d), 8.71 (2H,s), 9.11 (1H, s); MS (APCI⁺) found (M+1)=520; C28H33N5OS2 requires 519.

Example 2101-(9-Phenylnonyl)-2-(thien-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B91 by general method A2. ¹H-NMR (CDCl₃) δ1.28 (10H, m), 1.64 (4H, m), 2.60 (2H, t), 3.75 (4H, m), 4.73 (2H, s),6.94 (2H, m), 7.09 (1H, m), 7.15-7.27 (6H, m), 8.73 (2H, s), 9.10 (1H,s); MS (APCI⁺) found (M+1)=519; C₂₉H₃₄N₄OS₂ requires 518.

Example 2111-(9-Phenylnonyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B91 by general method A2. ¹H-NMR (CDCl₃) δ1.28 (10H, m), 1.60 (4H, m), 2.59 (2H, t), 3.71 (4H, m), 4.44 (2H, s),6.95 (1H, s), 7.10-7.27 (8H, m), 8.70 (2H, s), 9.10 (1H, s); MS (APCI⁺)found (M+1)=549; C₃₁H₃₄F₂N₄OS requires 548.

Example 2121-(2-(2-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B117 by general method A2. ¹H-NMR (CDCl₃) δ0.87 (3H, t), 1.25 (4H, m), 1.45 (2H, m), 2.39 (2H, t), 3.04 (2H, t),3.50 (2H, s), 3.97 (2H, t), 4.52 (2H, s), 6.31 (1H, s), 6.94-7.21 (8H,m), 7.40 (2H, m), 8.50 (2H, s), 9.09 (1H, s), MS (APCI⁺) M+1=503,C₂₉H₃₁FN₄OS requires 502. MPt 112.3° C. (colourless solid).

Example 2131-(2-(3-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B116 by general method A2. ¹H-NMR (CDCl₃) δ0.89 (3H, m), 1.30 (4H, m), 1.50 (2H, m), 2.52 (2H, t), 2.98 (2H, t),3.51 (2H, s), 3.98 (2H, s), 3.98 (2H, t), 4.51 (2H, s), 6.41 (1H, s),6.80-7.16 (6H, m), 7.41 (2H, m), 8.49 (2H, s), 9.08 (1H, s), MS(APCI⁺)M+1=503, C₂₉H₃₁FN₄OS requires 502. MPt 93.2° C. (colourless solid).

Example 2141-(2-(4-Bromophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B114 by general method A2. ¹H-NMR (CDCl₃) δ2.97 (2H, t), 3.59 (2H, s), 3.95 (2H, t), 4.49 (2H, s), 6.50 (1H, s),6.89-7.05 (4H, m), 7.35-7.44 (4H, m), 8.58 (2H, s), 9.11 (1H, s),MS(APCI⁺) M+1=511, C₂₄H₂₀BrFN₄OS requires 510. MPt 151.6° C. (creamsolid).

Example 2151-(5-Methylfuran-2-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B98 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 1.64 (3H, s), 3.70 (2H, s), 4.49 (2H, s), 4.83(2H, s), 5.95 (1H, d), 6.28 (1H, d), 6.94-7.09 (3H, m), 7.33-7.45 (2H,m), 8.69 (2H, s), 9.09 (1H, s), MS (APCI⁺) found (M+1)=423; C₂₂H₁₉FN₄O₂Srequires 422.

Example 2161-(2-(2-Chlorophenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B100 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 3.10-3.23 (2H, t), 3.51 (2H, s), 4.00-4.12 (2H,t), 4.51 (2H, t), 6.42 (1H, s), 6.90-7.48 (8H, m), 8.48 (2H, s), 9.09(1H, s); MS (APCI⁺) found (M+1) 467; C₂₄H₂₀ClFN₄OS requires 466.

Example 2171-(2-(Thien-2-yl)ethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B97 by general method A2. ¹H-NMR (CDCl₃) δ3.26 (2H, t), 3.55 (2H, s), 4.02 (2H, t), 4.48 (2H, s), 6.51 (1H, s),6.67 (1H, m), 6.91 (1H, m), 7.05-7.27 (4H, m), 8.53(2H, s) 9.09 (1H, s);MS (APCI⁺) found (M+1)=457; C₂₂H₁₈F₂N₄OS₂ requires 456.

Example 2181-(2-Phenylethyl)-2-(2,3,4-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A3 as a pale yellowfoam ¹H-NMR (CDCl₃) δ 3.02 (2H, t), 3.51 (2H, s), 3.99 (2H, t), 4.55(2H, s), 6.42 (1H, s), 6.8-7.1 (3H, m), 7.2-7.45 (4H, m), 8.48 (2H, s),9.09 (1H, s); MS (APCI⁺) found (M+1)=469; C₂₄H₁₉F₃N₄OS requires 468.

Example 2191-(2-Phenylethyl)-2-(2,3,5-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A3 as a white solid¹H-NMR (CDCl₃) δ 3.02 (2H, t), 3.52 (2H, s), 3.99 (2H, t), 4.51 (2H, s),6.40 (1H, s), 6.85-7.1 (3H, m) 7.2-7.35 (3H, m), 7.4-7.55 (1H, m), 8.5(2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=469; C₂₄ ₁₉F₃N₄OS requires468.

Example 2201-(2-Phenylethyl)-2-(2,4,6-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A3 as a white solid¹H-NMR (CDCl₃) δ 3.02 (2H, t), 3.51 (2H, s), 3.99 (2H, t), 4.60 (2H, s),6.38 (1H, s), 6.6-6.8 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (3H, m), 8.48(2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=469; C₂₄H₁₉F₃N₄OS requires468.

Example 2211-(2-Phenylethyl)-2-(2,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 2.95-3.08 (2H, t), 3.51 (2H, s), 3.94-4.05 (2H,t), 4.54 (2H, s), 6.39 (1H, s), 6.74-6.91 (2H, m), 6.95-7.06 (2H, m),7.18-7.34 (3H, m), 7.52-7.67 (1H, m), 8.48 (2H, s), 9.09 (1H, s); MS(APCI⁺) found (M+1)=451; C₂₄H₂₀F₂N₄OS requires 450.

Example 2221-(2-Phenylethyl)-2-(2-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2. ¹H-NMR (CDCl₃) δ2.95-3.09 (2H, t), 3.49 (2H, s), 3.92-4.06 (2H, t), 4.59 (2H, s), 6.38(1H, s), 6.94-7.37 (8H, m), 7.50-7.63 (1H, t), 8.49 (2H, s), 9.08 (1H,s), MS (APCI⁺) found (M+1)=433; C₂₄H₂₁FN₄OS requires 432.

Example 2231-(2-Phenylethyl)-2-furfurylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2. ¹H-NMR (CDCl₃) δ3.03 (2H, t), 3.51 (2H, s), 4.00 (2H, t), 4.62 (2H, s), 6.41 (3H, m),7.03 (2H, m), 7.27 (3H, m), 7.38 (1H, m), 8.46 (2H, s), 9.09 (1H, s); MS(APCI⁺) found (M+1)=405; C₂₂H₂₀N₄O₂S requires 404.

Example 2241-(2-Phenylethyl)-2-(thien-2-ylmethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2. ¹H-NMR (CDCl₃) δ3.03 (2H, t), 3.51 (2H, s), 3.99 (2H, t), 4.78 (2H, s), 6.36 (1H, s),6.93-7.02 (3H, m), 7.12 (1H, m), 7.22-7.28 (4H, m), 8.48 (2H, s), 9.09(1H, s); MS (APCI⁺) found (M+1)=421; C₂₂H₂₀N₄OS₂ requires 420.

Example 2251-(2-Phenylethyl)-2-(3,4,5-trifluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A3 as a pale yellowfoam. ¹H-NMR (CDCl₃) δ 3.03 (2H, t), 3.52 (2H, s), 4.02 (2H, t), 4.45(2H, s), 6.46 (1H, s), 6.95-7.2 (4H, m), 7.2-7.4 (3H, m), 8.49 (2H, s),9.09 (1H, s); MS (APCI⁺) found (M+1)=469; C₂₄H₁₉F₃N₄OS requires 468.

Example 2261-(2-Phenylethyl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2. ¹H-NMR (CDCl₃) δ2.95-3.10 (2H, t), 3.52 (2H, s), 3.95-4.07 (2H, t), 4.49 (2H, s), 6.39(1H, s), 6.96-7.36 (8H, m), 8.48 (2H, s), 9.09 (1H, s); MS (APCI⁺) found(M+1)=451; C₂₄H₂₀F₂N₄OS require 450.

Example 2271-(2-Phenylethyl)-2-(3,5-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 2.97-3.10 (2H, t), 3.52 (2H, s), 3.95-4.16 (2H,t), 4.51 (2H, s), 6.40 (1H, s), 6.66-6.80 (1H, m), 6.89-7.08 (4H, m),7.18-7.37 (3H, m), 8.49 (2H, s), 9.09 (1H, s); MS (APCI⁺) found(M+1)=451; C₂₄H₂₀F₂N₄OS requires 450.

Example 2281-(2-Phenylethyl)-2-(3-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 2.95-3.09 (2H, s), 3.52 (2H, s), 3.94-4.07 (2H,t), 4.53 (2H, s), 6,39 (1H, s), 6.90-7.38 (9H, m), 8.48 (2H, s), 9.09(1H, s); MS (APCI⁺) found (M+1)=433; C₂₄H₂₁FN₄OS. requires 432.

Example 2291-(2-Phenylethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B93 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 2.98-3.10 (2H, t), 3.49 (2H, s), 3.944.06 (2H,s), 4.51 (2H, s), 6.39 (1H, s), 6.94-7.08 (4H, m), 7.20-7.33 (3H, m),7.36-7.48 (2H, m), 8.48 (2H, s), 9.09 (1H, s); Ms (APCI⁺) found(M+1)=433; C₂₄H₂₁FN₄OS requires 432.

Example 2301-(2-Phenylethyl)-2-(1-phenylethyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from intermediate B93 by general method A2 as a pale yellowsolid. ¹H-NMR (CDCl₃) δ 1.82 (2H, t), 2.99 (2H, t), 3.50 (2H, s),3.85-4.1 (2H, m), 5.35 (1H, q), 6.34 (1H, s), 6.9-7.05 (2H, m), 7.15-7.5(8H, m), 8.49 (2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=429;C₂₅H₂₄N₄OS requires 428.

Example 2311-(2-(4-Methoxyphenyl)ethyl)-2-(3,4-difluorobenzyl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B134 by general method A2 as a white solid.¹H-NMR (CDCl₃) δ 2.91-3.02 (2H, t), 3.59 (2H, s), 3.84 (3H, s),3.90-4.02 (2H, t), 4.48 (2H, s), 6.42 (1H, s), 6.73-7.31 (7H, m), 8.51(2H, s), 9.10 (1H, s); MS (APCI⁺) found (M+1)=481; C₂₅H₂₂F₂N₄O₂Srequires 480.

Example 2321-(2-(4-Pent-1-ylphenyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B112 by general method A2. ¹H-NMR (CDCl₃) δ0.88 (3H, t), 1.32 (4H, m), 1.60 (2H, m), 2.60 (2H, m), 2.97 (2H, m),3.52 (2H, s), 3.97 (2H, t), 4.51 (2H, s), 6.46 (1H, s), 6.84-7.11 (6H,m), 7.40 (2H, m), 8.50 (2H, s), 9.08 (1H, s); MS(APCI⁺) M+1=503,C₂₉H₃₁FN₄OS requires 502. MPt 98.7° C. (colourless solid).

Example 2331-(Cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B105 by general method A2. ¹H-NMR (CDCl₃) δ0.94-1.32 (4H, m), 3.03-3.18 (1H, m), 3.69 (2H, s), 4.42 (2H, s),6.93-7.07 (2H, t), 7.14 (1H, s), 7.31-7.45 (2H, m), 8.70 (2H, s), 9.10(1H, s); MS (APCI⁺) found (M+1)=369; C₁₉H₁₇FN₄OS requires 368.

Example 2341-(Dodec-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B96 by general method A2 as an oil. ¹H-NMR(CDCl₃) δ 0.78-0.85 (3H, t), 1.13-1.70 (20H, m), 3.65-3.80 (4H, m), 4.45(2H, s), 6.92-7.27 (4H, s), 8.70 (2H, s), 9.11 (1H, s); MS (APCI⁺) found(M+1)=515; C₂₈H₃₆F₂N₄OS requires 514.

Example 2351-Ethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B89 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 1.30-1.44 (3H, t). 3.72 (2H, s), 3.75-3.90 (2H, q), 4.47 (2H,s), 6.94-7.17 (3H, m), 7.33-7.45 (2H, m), 8.70 (2H, s), 9.10 (1H, s); MS(APCI⁺) found (M+1)=357; C₁₈H₁₇FN₄OS requires 356.

Example 2361-(1-Methylethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B104 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 1.32-1.45 (6H, d), 3.73 (2H, s), 4.46 (2H, s), 4.49-4.65 (1H,m), 6.94-7.05 (2H, t), 7.17 (1H, s), 7.33-7.45 (2H, m), 8.72 (2H, s),9.10 (1H, s); MS (APCI⁺) found (M+1)=371; C₁₉H₁₉FN₄OS requires 370.

Example 2371-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B84 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 3.49 (3H, s), 3.71 (2H, s), 4.48 (2H, s) 6.93-7.07 (3H, m),7.32-7.44 (2H, m), 8.70 (2H, s), 9.10 (1H, s); MS (APCI⁺) found(M+1)=343; C₁₇H₁₅FN₄OS requires 342.

Example 2381-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B95 by general method A2 as an oil. ¹H-NMR(CDCl₃) δ 0.82-0.98 (3H, t), 1.13-1.80 (18H, m), 3.65-3.79 (4H, m), 4.47(2H, s), 6.90-7.07 (3H, m), 7.31-7.43 (2H, m), 8.70 (2H, s), 9.10 (1H,s); MS (APCI⁺) found (M+1)=483; C₂₇H₃₅FN₄OS requires 482.

Example 2391-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

To a solution of either Example 243 or 244 (0.2 g) in dry methylenechloride (4 ml) at 4° C. was added boron tribromide (1M in methylenechloride, 2 ml). The mixture was stirred under argon for 24 h and pouredinto a mixture of ice (50 ml) and 0.880 ammonia (15 ml) with stirring.Extraction with 5% methanol:methylene chloride was followed byfiltration through kieselguhr and drying the organic layer over sodiumsulphate. Removal of the solvent in vacuo gave the desired material as agrey solid (0.15 g). ¹H-NMR (CDCl₃) δ 0.8-0.95 (3H, m), 1.1-1.4 (16H,m), 1.6-1.85 (2H, m), 3.49 (2H, s), 3.79 (2, t), 4.45 (2H, s), 6.9-7.1(2H, m), 7.2-7.45 (3H, m), 8.32 (2H, s); MS (APCI⁺) found (M+1)=499;C₂₇H₃₅FN₄O₂S requires 498.

Example 2401-Benzyl-2-benzylthio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example B39 by alkylation with benzyl bromide usinggeneral method A4, followed by N-alkylation using general method C2.¹H-NMR (CDCl₃) δ 3.62 (2H, s), 3.98 (3H, s), 4.51 (2H, s), 4.96 (2H, s),6.92 (1H, s), 7.10 (1H, m), 7.23-7.40 (9H, m), 8.41 (2H, s); MS (APCI⁺)found (M+1)=431; C₂₄H₂₂N₄O₂S requires 430.

Example 2411-(2-Phenylethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 107 by general method C3. ¹H-NMR (CDCl₃) δ 3.01(2H, t), 3.46 (2H, s), 3.99 (2H, t), 4.01 (3H, s), 4.49 (2H, s), 6.33(1H, s), 6.99-7.29 (8H, m), 8.22 (2H, s); MS (APCI⁺) found (M+1)=481;C₂₅H₂₂F₂N₄O₂S requires 480.

Example 2421-(Furan-2-ylmethyl)-2-(3,4-difluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 107 by general method C3. ¹H-NMR (CDCl₃) δ 3.63(2H, s), 4.00 (3H, s), 4.46 (2H, s), 4.90 (2H, s), 6.38 (2H, m), 7.01(1H, s), 7.07-7.26 (3H, m), 7.42 (1H, m), 8.44 (2H, s); MS (APCI⁺) found(M+1)=457; C₂₂H₁₈F₂N₄O₃S requires 456.

Example 2431-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B124 by general method A2. ¹H-NMR (CDCl₃) δ0.88 (3H, t), 1.25 (16H, m), 1.68 (2H, m), 3.64 (2H, s), 3.71 (2H, t),4.00 (3H, s), 4.47 (2H, s), 6.87 (1H, s), 7.00 (2H, m), 7.36(2H, m),8.46(2H, s); MS (APCI⁺) found (M+1)=513; C₂₈H₃₇N₄O₂S requires 512.

Example 2441-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-ethoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B92 by general method A3 as an off-whitesolid. ¹H-NMR (CDCl₃) δ 0.8-0.95 (3H, m), 1.15-1.4 (16H, m), 1.43 (3H,t), 1.55-1.8 (2H, m), 3.68 (2H, s), 3.71 (2H, t), 4.41 (2H, q), 4.47(2H, s), 6.86 (1H, s), 6.9-7.1 (2H, m), 7.3-7.45 (2H, m), 8.45 (2H, d);MS (APCI⁺) found (M+1)=527; C₂₉H₃₉FN₄O₂S requires 526.

Example 2451-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(2-methylpyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B135 by general method A2. ¹H-NMR (CDCl₃) δ0.88 (3H, t), 1.25 (16H, m), 1.68 (2H, m), 2.72 (3H, s), 3.68 (2H, s),3.72 (2H, t), 4.47 (2H, s), 6.89 (1H, s), 6.97 (2H, m), 7.38 (2H, m),8.58(2H, s); MS (APCI⁺) found (M+1)=497; C₂₈H₃₇N₄OS requires 496.

Example 2461-(2-Phenylethyl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B70 by general method A2. ¹H-NMR (CDCl₃) δ3.01 (2H, t), 3.40 (2H, s), 3.51 (3H, s), 3.97 (2H, t), 4.51 (2H, s),6.02 (1H, m), 6.24 (1H, s), 6.49 (1H, s), 6.98-7.43 (10H, m); MS (APCI⁺)M+1=462; C₂₆H₂₄FN₃O₂S requires 461. MPt 69-75° C. (cream solid).

Example 2471-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B110 by general method A2. ¹H-NMR (CDCl₃) δ0.88 (3H, t), 1.25 (16H, m), 1.69 (2H, m), 3.50 (3H, s), 3.55 (2H, s),3.71 (2H, t), 4.78 (2H, s), 6.17 (1H, m), 6.38 (1H, d), 6.84 (1H, s),6.96 (2H, m), 7.19 (1H, m), 7.39 (2H, m); MS (APCI⁺) M+1=512,C₂₉H₃₈FN₃O₂S requires 511. MPt 78-79° C. (colourless solid).

Example 2481-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5-(1-methyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 239 by treatment with methyl iodide (1 equiv) andpotassium carbonate (2 equiv) in DMF. The misture was stirred at roomtemperature for 16 hours, then at 50° C. for 1 hour. Evaporation of thesolvent, aqueous workup and chromatography gave the title compound in72% yield. ¹H-NMR (CDCl₃) δ 0.8-0.95 (3H, m), 1.15-1.4 (16H, m),1.6-1.85 (2H, m), 3.43 (2H, bs), 3.54 (3H, s), 3.78 (2H, t), 4.46 (2H,s), 6.9-7.1 (2H, m), 7.19 (1H, s), 7.25-7.45 (2H, m), 8.01 (1H, bd),8.46 (1H, m).

Example 249 1-(Undec-1-yl)-2-(4-fluorobenzyl)thio-5(1-benzyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 239 analogously to Example 248, using benzylbromide in place of methyl iodide. ¹H-NMR (CDCl₃) δ 0.8-0.95 (3H, m),1.15-1.4 (16H, m), 1.6-1.85 (2H, m), 3.39 (2H, s), 3.74 (2H, t), 4.46(2H, s), 5.08 (2H, s), 6.9-7.1 (3H, m), 7.25-7.45 (7H, m), 7.94 (1H, d),8.43 (1H, d); MS (APCI⁺) found (M+1)=589; C₃₄H₄₁FN₄O₂S requires 588.

Example 2501-(Undec-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B95 by general method A4. ¹H-NMR (CDCl₃) δ0.88 (3H, t), 1.25 (16H, br s), 1.71 (2H, m), 3.71 (2H, s), 3.74 (2H,m), 4.49 (2H, s), 7.04 (1H, s), 7.26-7.41 (5H, m), 8.69 (2H, s), 9.09(1H, s); MS (APCI) found (M+H)=465; C₂₇H₃₆N₄OS requires 464.

Example 2511-Methyl-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)-pyrimidin-4-one

Prepared from Example 108 by general method C2. ¹H-NMR (CDCl3) δ 3.47(3H, s), 3.64 (2H, t), 3.99 (3H, s), 4.47 (2H, s), 6.88 (1H, s), 6.9-7.1(2H, m), 7.3-7.5 (2H, m), 8.44 (2H, s); MS (APCI+) found (M+1) 373;C₁₈H₁₇FN₄O₂S requires 372.

Example 2521-Methyl-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

To a solution of Example 251 (5 g) in dry methylene chloride was added asolution of boron tribromide 1M in dichloromethane (50 ml) at 5° C.under argon with stirring. After 0.5 h, the mixture was allowed to warmto room temperature and was allowed to stir at room temperature for 72h. The mixture was decanted into a mixture of ice (50 ml) and 0.880ammonia (50 ml). The solid remaining in the flask was treated with someof the aqueous mixture and 10% methanol in methylene chloride. Theentire mixture was filtered through kieselguhr and the organic layer wasseparated. The aqueous layer was reduced to one quarter volume in vacuoand the solid formed filtered off, washed with water and dried in vacuoto give the desired product (2.2 g). ¹H-NMR (d₆ DMSO) δ 3.30 (2H, s),3.47 (3H, s), 4.41 (2H, s), 7.05-7.25 (2H, m), 7.4-7.55 (2H, m), 7.65(1H, s), 7.85-8.3 (2H, b): MS (APCI+) found (M+1) 359; C₁₇H₁₅FN₄O₂Srequires 358.

Example 2531-(4-Acetylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one

Prepared from intermediate B136 by general method A4. ¹H-NMR (CDCl₃) δ2.64(3H, s), 3.79(2H, s), 4.39(2H, s), 6.95(2H, m), 7.05(1H, s),7.29(2H, m), 7.43(2H, d, j=8.5 Hz), 8.08(2H, d, j=8.5), 8.75(2H, s),9.09(1H, s): MS (APCI) found (M+H)=447; C₂₄H₁₉FN₄O₂S requires 446.

Example 2541-(3-(Non-1-yloxy)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B128 by general method A2. ¹H-NMR (CDCl₃) δ9.08 (1H, s), 8.73 (2H, s), 7.41-7.28 (3H, m), 7.09 (1H, s), 7.03-6.78(5H, m), 4.36 (2H, s), 3.95 (2H, t), 3.73 (2H, s), 1.78 (2H, quintet),1.47-1.23 (12H, m), 0.88 (3H, t); MS (APCI+) found (M+1)=547,C₃₁H₃₅FN₄O₂S requires 546.

Example 2551-(3-(Dec-1-yl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B129 by general method A2. ¹H-NMR (CDCl₃) δ9.08 (1H, s), 8.73 (2H, s), 7.40-7.27 (4H, m), 7.11-7.08 (3H, m), 6.94(2H, t), 4.35 (2H, s), 3.73 (2H, s), 2.65 (2H, t), 1.67-1.56 (2H, m),1.30-1.22 (14H, m), 0.88 (3H, t); MS (APCI+) found (M+1)=545,C₃₂H₃₇FN₄OS requires 544.

Example 2561-Methyl-2-(4-fluorobenzyl)thio-5-(1-undecyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 252 and undecyl iodide by the method of Example248. ¹H-NMR (CDCl3) δ 0.88 (3H, s), 1.2-1.4 (16H, m), 1.77 (2H, m), 3.43(2H, s), 3.53 (3H, s), 3.86 (2H, t), 4.47 (2H, s), 6.9-7.1 (2H, m), 7.20(1H, s), 7.3-7.45 (2H, m), 7.96 (1H, d), 8.44 (1H, d); MS (APCI+) found(M+1)=513; C₂₈H₃₇FN₄O₂S requires 512.

Example 2571-Phenyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B121 by general method A2. ¹H NMR (CDCl₃) δ:3.74 (s, 2H), 4.36 (s, 2H), 6.95 (t, 2H), 7.06 (s, 1H), 7.30 (m, 4H),7.55 (m, 3H), 8.72 (s, 2H), 9.10 (s, 1H). MS (APCI+) Found (M+1)=405;C₂₂H₁₇FN₄OS requires 404.

Example 2581-Phenyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B121 by general method A2. ¹H NMR (CDCl₃) δ:1.35 (m, 6H), 1.65 (m, 4H), 2.91 (t, 2H), 3.14 (t, 2H), 3.76 (s, 2H),7.04 (s, 1H), 7.3 (m, 2H), 7.43 (d, 2H), 7.55 (m, 3H), 7.89 (d, 2H),8.72 (s, 2H), 9.10 (s, 1H). MS (APCI+) Found (M+1)=533/535;C₂₉H₂₉ClN₄O₂S requires 533.

Example 2591-(4-(Non-1-yloxyphenyl))-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B126 by general method A2. ¹H-NMR (CDCl₃) δ9.07 (1H, s), 8.73 (2H, s), 7.30 (2H, dd), 7.21 (2H, d), 7.13 (1H, s),6.95 (2H, d), 6.94 (2H, t), 4.33 (2H, s), 3.97 (2H, t), 3.73 (2H, s),1.79 (2H, quintet), 1.47-1.23 (12H, m), 0.88 (3H, t); MS (APCI+) found(M+1)=547, C₃₁H₃₅FN₄O₂S requires 546.

Example 2601-(4-Iodophenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B130 by general method A2. ¹H-NMR(CDCl₃+CD₃OD) δ 9.08 (1H, s), 8.72 (2H, s), 7.85 (2H, d), 7.33-7.26 (2H,m), 7.07 (1H, s), 7.05 (2H, d), 6.98 (2H, t), 4.35 (2H, s), 3.73 (2H,s); MS (APCI+) found (M+1)=531, C₂₂H₁₆FIN₄OS requires 530.

Example 2611-(4-(Hex-1-yl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B127 by general method A2. ¹H-NMR (CDCl₃) δ9.08 (1H, s), 8.73 (2H, s), 7.33-7.27 (4H, m), 7.19 (2H, d), 7.09 (1H,s), 6.94 (2H, t), 4.35 (2H, s), 3.73 (2H, s), 2.66 (2H, t), 1.62 (2H,quintet), 1.39-1.27 (6H, m), 0.87 (3H, t); MS (APCI+) found (M+1)=489,C₂₈H₂₉FN₄OS requires 488.

Example 2621-(4-(Dec-1-yl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B125 by general method A2. ¹H-NMR (CDCl₃) δ9.08 (1H, s), 8.73 (2H, s), 7.33-7.27 (4H, m), 7.19 (2H, d), 7.10 (1H,s), 6.94 (2H, t), 4.35 (2H, s), 3.73 (2H, s), 2.65 (2H, t), 1.67-1.56(2H, m), 1.34-1.22 (14H, m), 0.88 (3H, t); MS (APCI+) found (M+1)=545,C₃₂H₃₇FN₄OS requires 544.

Example 2631-Ethoxycarbonylmethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B80 and A1 by general method A4, as a lightbrown crystalline solid. MPt 100-102° C.; ¹H-NMR (CDCl₃) δ 1.30 (3H, t),1.37 (6H, m), 1.70 (4H, m), 2.93 (2H, t), 3.26 (2H, t), 3.71 (2H, s),4.28 (2H, q), 4.50 (2H, s), 6.90 (1H, s), 7.44 (2H, m), 7.90 (2H, m),8.71 (2H, s), 9.10 (1H, s); MS APCI+) found (M+1)=543; C₂₇H₃₁ClN₄O₄Srequires 542.

Example 2641-(3-Ethoxycarbonylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B50 and A1 by general method A4, as a brownoil. ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.38 (6H, m), 1.69 (4H, m), 2.05(2H, m), 2.38 (2H, t), 2.93 (2H, t), 3.25 (2H, t), 3.70 (2H, s), 3.88(2H, t), 4.12 (2H, q), 7.05 (1H, s), 7.42 (2H, d), 7.91 (2H, d), 8.72(2H, s), 9.09 (1H, s); MS (APCI+) found (M+1)=571; C₂₉H₃₅ClN₄O₄Srequires 570.

Example 2651-(3-Ethoxycarbonylprop-1-yl)-2-benzylthio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B50 by general method A4, as a brown oil.¹H-NMR (CDCl₃) δ 1.24 (3H, t), 2.01 (2H, m), 2.35 (2H, m), 3.71 (2H, s),3.86 (2H, t), 4.12 (2H, q), 4.50 (2H, s), 7.07 (1H, s), 7.27-7.41 (5H,m), 8.72 (2H, s), 9.12 (1H, s); MS (APCI+) found (M+1)=425; C₂₂H₂₄N₄O₃Srequires 424.

Example 2661-(3-Ethoxycarbonylprop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B50 by general method A2 as an oil. ¹H-NMR(CDCl₃) δ 1.17-1.30 (3H, m), 1.96-2.12 (2H, m), 2.30-2.41 (2H, t), 3.70(2H, s), 3.70 (2H, s), 3.80-3.90 (2H, t), 4.06-4.20 (2H, q), 4.49 (2H,s), 7.01-7.26 (4H, m), 8.72 (2H, s), 9.10 (1H, s); MS (ES+) found(M+1)=461; C₂₂H₂₂F₂N₄O₃S requires 460.

Example 2671-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B50 by general method A2. ¹H-NMR (CDCl₃) δ1.26 (3H, t), 2.03 (2H, m), 2.35 (2H, t), 3.70 (2H, s), 3.85 (2H, t),4.12 (2H, m), 4.47 (2H, s), 6.71-7.07 (3H, m), 7.35-7.41 (2H, m), 8.70(2H, s), 9.10 (1H, s); MS (APCI⁺) M+1=443, C₂₂H₂₃FN₄O₃S requires 442(orange oil).

Example 2681-(5-Ethoxycarbonylpent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B102 by general method A2 as an oil. ¹H-NMR(CDCl₃) δ 1.14-1.87 (9H, m), 2.25-2.37 (2H, m), 3.63-3.82 (4H, m),4.04-4.19 (2,q), 4.45 (2H, s), 6.97-7.30 (4H, m), 8.70 (2H, s), 9.10(1H, s); MS (ES+) found (M+1)=489; C₂₄H₂₆F₂N₄O₃S requires 488.

Example 2691-(1-(Ethoxycarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B106 by general method A2 as a foam. ¹H-NMR(CDCl₃) δ 1.08-1.20 (3H, t), 1.38-1.54 (1H, m), 1.58-1.85 (2H, m),1.94-2.10 (1H, m), 3.71 (2H, s), 4.04-4.28 (2H, m), 4.35-4.52 (2H, q),6.90-7.05 (2H, t), 7.08 (1H, s), 7.29-7.42 (2H, m), 8.70 (2H, s), 9.10(1H, s); MS (APCI⁺) found (M+1)=441; C₂₂H₂₁FN₄O₃S requires 440.

Example 2701-(4-Fluorobenzyloxycarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B80 by alkaline hydrolysis as in generalmethod D, followed by alkylation with 4-fluorobenzyl bromide by generalmethod A2. ¹H-NMR (CDCl₃) δ 3.71 (2H, s), 4.46 (4H, m), 5.16 (2H, s),6.87 (1H, s), 6.94-7.06 (4H, m), 7.25-7.35 (4H, m) 8.68 (2H, s), 9.10(1H, s); MS(APCI⁺) M+1=495, C₂₅H₂₀F₂N₄O₃S requires 494. MPt 184-186° C.(colourless solid). MPt. 184-186

Example 2711-Ethoxycarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B80 by general method A2. ¹H-NMR (CDCl₃) δ1.26 (3H, t), 3.71 (2H, s), 4.26 (2H, q), 4.46 (2H, s), 4.48 (2H, s),6.91 (1H, s), 6.98 (2H, m), 7.35 (2H, m), 8.70 (2H, s), 9.09 (1H, s);MS(APCI⁺) M+1=415, C₂₀H₁₉FN₄O₃S requires 414. MPt 145.1 ° C. (yellowsolid).

Example 2721-(1-(Methoxycarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B103 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 1.68 (3H, d), 3.70 (2H, s), 3.78 (3H, s), 4.38-4.58 (2H,br.q), 4.98-5.10 (1H, q), 6.95-7.07 (2H, t), 7.19 (1H, s), 7.30-7.42(2H, m), 8.72 (2H, s), 9.10 (1H, s); MS (APCI⁺) found (M+1)=429,C₂₀H₁₉FN₄O₃S requires 428.

Example 2731-(trans-4-(Methoxycarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B137 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 0.88-1.11 (2H, m), 1.30-1.54 (2H, m), 1.60-1.82 (4H, m),1.94-2.13 (1H, m), 2.14-2.34 (1H, m), 3.53-3.74 (7H, m), 4.46 (2H, s),6.90 (1H, s), 6.94-7.08 (2H, t), 7.30-7.44 (2H, m), 8.70 (2H, s), 9.11(1H, s); MS (APCI⁺) found (M+1)=483; C₂₅H₂₇FN₄O₃S requires 482.

Example 2741-(trans-4-(Methoxycarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B108 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 1.54-1.97 (6H, m), 2.22-2.39 (2H, d), 2.68-2.79 (1H, br.s),3.70 (2H, s), 3.73 (3H, s), 4.03-4.25 (1H, m), 4.45 (2H, s), 6.93-7.08(2H, m), 7.21 (1H, s), 7.30-7.43 (2H, m), 8.71 (2H, s), 9.08 (1H, s). MS(APCI⁺) found (M+1)=469; C₂₄H₂₅FN₄O₃S requires 468.

Example 2751-(3-Ethoxycarbonylprop-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from intermediate B111 by general method A2. ¹H-NMR (CDCl₃) δ1.25 (3H, t), 2.02 (2H, m), 2.35 (2H, t), 3.50 (3H, s), 3.54 (2H, s),3.83 (2H, t), 4.12 (2H, q), 4.47 (2H, s), 6.19 (1H, m), 6.37 (1H, s),6.84-7.41 (6H, m). MS (APCI⁺) M+1=472; C₂₄H₂₆FN₃O₄S requires 471. MPt109-111° C. (colourless solid). MPt. 109-111

Example 2761-(Ethoxycarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 108 by general method C2. ¹H-NMR (CDCl₃) δ 1.26(3H, t), 3.66 (2H, s), 3.99 (3H, s), 4.23 (2H, q), 4.47 (2H, s), 4.48(2H, s), 6.84 (1H, s), 6,98 (2H, m), 7.34 (2H, m), 8.44 (2H, s); MS(APCI+) found (M+1)=445; C₂₁H₂₁FN₄O₄S requires 444.

Example 2771-(4-(Ethoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-methyl)pyrimidin-4-one

Prepared from intermediate B107 by general method A2 as a solid. ¹H-NMR(CDCl₃) δ 1.35-1.47 (3H, t), 3.70 (2H, s), 3.93 (1H, s), 4.32-4.52 (3H,m), 5.02 (2H, s), 6.90-7.06 (3H, m), 7.13-7.40 (4H, m), 7.98-8.10 (2H,d), 8.67 (2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=491; C₂₆H₂₃FN₄O₃Srequires 490.

Example 2781-(4-Methoxycarbonylbenzyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 70 by general method C1. ¹H-NMR (CDCl₃) δ1.2-1.45(8H, m), 1.45-1.75(4H, m), 2.55(2H, t), 3.24(2H, t), 3.73(2H,s), 3.92(3H, s), 5.01(2H, s), 6.81(1H, s), 7.05-7.3(7H, m), 7.61(1H,txd), 8.03(2H, d) and 8.46(2H, bs); MS (EI) found M=589; C₃₃H₃₆ClN₃O₃Srequires 589.

Example 2791-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 267 by general method D. ¹H-NMR (d₆-DMSO) δ 1.93(2H, m), 2.29 (2H, t), 3.58 (2H, s), 3.87 (2H, t), 4.40 (2H, s), 7.14(2H, m), 7.48 (2H, m), 7.81 (1H, s), 8.70 (2H, s), 9.02 (1H, s); MS(APCI−) M−1=413, C₂₀H₁₉FN₄O₃S requires 414. MPt 188-190° C. (colourlesssolid).

Example 2801-Carboxymethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 271 by general method D. ¹H-NMR (d₆-DMSO) δ 3.59(2H, s), 4.41 (2H, s), 4.67 (2H, s), 7.11 (2H, m), 7.45 (2H, m), 7.72(1H, s), 8.70 (2H, s), 9.03 (1H, s), 13.55 (1H, bs); MS (APCI−) M−1=385,C₁₈H₁₅FN₄O₃S requires 386. MPt 206-207° C. (colourless solid).

Example 2811-(3-Carboxyprop-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 275 by general method D. ¹H-NMR (d₆-DMSO) δ 1.90(2H, m), 2.28 (2H, t), 3.37 (5H, m), 3.86 (2H, t), 4.41 (2H, s), 6.12(1H, m), 6.18 (1H, s), 7.14 (2H, m), 7.50 (3H, m), 7.73 (1H, s), 12.2(1H, bm); MS (APCI⁺) M+1=444, C₂₂H₂₂FN₃O₄S requires 443. MPt 245-249° C.(colourless solid).

Example 2821-(3-Carboxyprop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 266 by general method D as a white solid. ¹H-NMR(DMSO) δ 1.83-2.03 (2H, m), 2.24-2.37 (2H, t), 3.58 (2H, s), 3.81-3.93(2H, t), 4.41 (2H, s), 7.23-7.59 (3H, m), 7.81 (1H, s), 8.71 (2H, s),9.02 (1H, s), 12.13-12.20 (1H, s); MS (APCI−) found (M−1) 431;C₂₀H₁₈F₂N₄O₃S requires 432.

Example 2831-(5-Carboxypent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 268 by general method D as a white solid. ¹H-NMR(DMSO) δ 1.18-1.81 (6H, m), 2.14-2.29 (2H, t), 3.59 (2H, s), 3.76-3.90(2H, t), 4.41 (2H, s), 7.23-7.60 (3H, m), 7.85 (1H, s), 8.70 (2H, s),9.02 (1H, s), 11.92-12.10 (1H, s); MS (APCI−) found (M−1)=459;C₂₂H₂₂F₂N₄O₃S requires 460.

Example 284 1-(4-Carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared from Example 277 by general method D. ¹H-NMR (DMSO) δ 3.60 (2H,s), 4.39 (2H, s), 5.21 (2H, s), 7.03-7.19 (2H, t), 7.26-7.49 (4H, m),7.38-8.02 (3H, m), 8.72 (2H, s), 9.03 (1H, s), 12.92-13.10 (1H, br.s);MS (APCI+) found (M+1)=463; C₂₄H₁₉FN₄O₃S requires 462.

Example 2851-(4-Carboxycyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-2-thiouracil

Prepared from Example 274 by general method D. ¹H-NMR (DMSO) δ 1.57-1.88(6H, m), 2.13-2.26 (2H, d), 2.60 (1H, s), 3.62 (2H, s), 3.98-4.10 (1H,m), 4.40 (2H, s), 7.09-7.19 (2H, t), 7.44-7.53 (2H, m), 8.00 (1H, s),8.72 (2H, s), 9.00 (1H, s), 12.27 (1H, s); MS (APCI+) found (M+1)=455;C₂₃H₂₃FN₄O₃S requires 454.

Example 2861-(3-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B118 by general method A2. H NMR (CDCl₃) δ:1.41 (t, 3H), 3.75 (s, 2H), 4.37 (s, 2H), 4.41 (q, 2H), 6.95 (t, 2H),7.05 (s, 1H), 7.30 (m, 2H), 7.50 (m, 1H), 7.60 (t, 1H), 7.97 (m, 1H),8.21 (d, 1H), 8.72 (s, 2H), 9.10 (s, 1H); MS (APCI+) Found (M+1)=477;C₂₅H₂₁FN₄O₃S requires 476.

Example 2871-(3-Ethoxycarbonylphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B118 by general method A4. ¹H NMR (CDCl₃) δ:1.3 (m, 6H), 1.42 (t, 3H), 1.65 (m, 4H), 2.91 (t, 2H), 3.15 (t, 2H),3.73 (s, 2H), 4.42 (q, 2H), 7.03 (s, 1H), 7.42 (d, 2H), 7.5 (m, 1H),7.62 (t, 1H), 7.88 (d, 2H), 7.98 (s, 1H), 8.22 (d, 1H), 8.72 (s, 2H),9.09 (s, 1H); MS (APCI+) Found (M+1)=605/607; C₃₂H₃₃ClN₄O₄S requires605.

Example 2881-(3-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 286 by general method D as a white solid, m.p157-160. ¹HNMR (DMSO-d₆) δ: 3.62 (s, 2H), 4.31 (s, 2H), 7.10 (t, 2H),7.40 (m, 2H), 7.70 (t, 1H), 7.87 (d, 1H), 7.94 (s, 1H), 8.10 (m, 2H),8.77 (s, 2H), 9.01 (s, 1H), 13.4 (br s, 1H); MS (APCI+) Found (M+1)=449;C₂₃H₁₇FN₄O₃S requires 448.

Example 2891-(3-Carboxyphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 287 by general method D as a white solid, m.p109-112°. ¹H NMR (DMSO-d₆) δ: 1.3 (m, 6H), 1.65 (m, 4H), 2.9-3.1 (m,4H), 3.60 (s, 2H), 7.57 (d, 2H), 7.71 (t, 1H), 7.8-8.0 (m, 4H), 8.13 (m,2H), 8.75 (s, 2H), 9.02 (s, 1H) 13.35 (br s, 1H). MS (APCI+) Found(M+1)=577/579; C₃₀H₂₉ClN₄O₄S requires 577.

Example 2901-(4-Ethoxycarbonylphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B119 by general method A2. ¹H NMR (CDCl₃) δ:1.40 (t, 3H), 3.74 (s, 2H), 4.37 (s, 2H), 4.41 (q, 2H), 6.95 (t, 2H),7.05 (s, 1H), 7.30 (m, 2H), 7.40 (d, 2H), 8.20 (d, 2H), 8.72 (s, 2H),9.11 (s, 1H). MS (APCI+) Found (M+1)=477; C₂₅H₂₁FN₄O₃S requires 476.

Example 2911-(4-Ethoxycarbonylphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B119 by general method A4. ¹H NMR (CDCl₃) δ:1.3 (m, 6H), 1.42 (t, 3H), 1.65 (m, 4H), 2.91 (t, 2H), 3.15 (t, 2H),3.73 (s, 2H), 4.44 (q, 2H), 7.03 (s, 1H), 7.4 (m, 4H), 7.88 (d, 2H),8.20 (d, 2H), 8.71 (s, 2H), 9.10 (s, 1H). MS (APCI+) Found(M+1)=605/607; C₃₂H₃₃ClN₄O₄S requires 605.

Example 2921-(4-Carboxyphenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 290 by general method D as a white solid,m.p.258-262° dec. ¹HNMR (DMSO-d₆) δ: 3.63 (s, 2H), 4.31 (s, 2H), 7.10(t, 2H), 7.40 (m, 2H), 7.74 (d, 2H), 7.95 (s, 1H), 8.10 (d, 2H), 8.77(s, 2H), 9.01 (s, 1H), 13.3 (br s, 1H). MS (APCI+) Found (M+1)=449;C₂₃H₁₇FN₄O₃S requires 448.

Example 2931-(4-Carboxyphenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 291 by general method D as a white solid, m.p92-96° C. ¹H NMR (DMSO-d₆) δ: 1.3 (m, 6H), 1.6 (m, 4H), 2.9-3.1 (m, 4H),3.61 (s, 2H), 7.57 (d, 2H), 7.74 (d, 2H), 7.95 (m, 3H), 8.10 (d, 2H),8.75 (s, 2H), 9.02 (s, 1H) 13.35 (br s, 1H). MS (APCI+) Found(M+1)=577/579; C₃₀H₂₉ClN₄O₄S requires 577.

Example 2941-(5-(Ethoxycarbonyl)fur-2-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B120 by general method A2. ¹H NMR (CDCl₃) δ:1.38 (t, 3H), 3.72 (s, 2H), 4.38 (s, 2H), 4.39 (q, 2H), 6.60 (d, 1H),6.97 (t, 2H), 7.08 (s, 1H), 7.20 (d, 1H), 7.3 (m, 2H), 8.71 (s, 2H),9.11 (s, 1H). MS (APCI+) Found (M+1) 467; C₂₃H₁₉FN₄O₄S requires 466.

Example 2951-(3-Ethoxycarbonyl-4-iodobenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. ¹H-NMR(250 MHz, DMSO) 9.03 (s, 1H), 8.82 (s, 2H), 8.00 (m, 2H), 7.57 (s, 1H),7.42 (m, 2H), 7.11 (m, 3H), 5.14 (s, 2H), 4.39 (s, 2H), 3.87 (s, 3H),3.62 (s, 2H). MS (AP+) 603 (M+H⁺, 100%).

Example 2961-(3-(Hept-1-yloxy)-4-methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. ¹H-NMR(400 MHz, CDCl₃) 9.00 (s, 1H), 8.61 (s, 2H), 7.53 (d, 1H), 7.30 (d, 1H),7.28 (d, 1H), 7.15 (dd, 1H), 6.90 (m, 4H), 4.82 (s, 2H), 4.40 (s, 2H),3.96 (t, 2H), 3.82 (s, 3H), 3.60 (s, 2H), 1.73 (m, 2H), 1.42 (m, 2H),1.29 (m, 6H), 0.83 (t, 3H). MS (AP+) 591 (M+H⁺, 100%).

Example 2971-(3-(Hept-1-yloxy)-4-methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. ¹H-NMR(400 MHz, CDCl₃) 9.00 (S, 1H), 8.59 (s, 2H), 7.68 (d, 1H), 7.29 (d, 1H),7.28 (d, 1H), 6.91 (m, 3H), 6.59 (s, 2H), 4.88 (s, 2H), 4.40 (s, 2H),3.81 (m, 5H), 3.62 (s, 2H), 1.72 (m, 2H), 1.40 (m, 2H), 1.28 (6H) 0.83(t, 3H). MS (AP+) 591 (M+H⁺, 100%).

Example 2981-(3-Carboxy-4-(hept-1-yloxy)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-ylmethyl)pyrimidin-4-one

Prepared from Example 296 by general method D as a colourless solid.¹H-NMR (250 MHz, CDCl₃) 9.05 (s, 1H), 8.75 (s, 2H), 8.65 (br s, 1H),8.02 (d, 1H), 7.32 (m, 4H), 6.98 (m, 3H), 4.99 (s, 2H), 4.40 (s, 2H),4.21 (t, 2H), 3.70 (s, 2H), 1.88 (m, 2H), 1.50-1.20 (m, 8H), 1.20 (m,8H), 0.87 (t, 3H). MS (AP+) 577 (M+H⁺, 100%).

Example 2991-(3-(Hept-1-yloxy)4-carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 297 by general method D as a colourless solid.¹H-NMR (400 MHz, CDCl₃) 9.04 (s, 1H), 8.67 (s, 2H), 8.11 (d, 1H), 7.33(d, 1H), 7.31 (d, 1H), 7.05 (s, 1H), 6.95 (t, 2H), 6.82 (d, 1H), 6.68(s, 1H), 4.99 (s, 2H), 4.44 (s, 2H), 4.05 (t, 2H), 3.69 (s, 2H), 1.87(m, 2H), 1.50-1.25 (m, 8H), 0.87 (t, 3H). MS (AP+) 577 (M+H⁺, 55%).

Example 3001-(3-Methoxycarbonyl-4-hydroxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. 1H-NMR(250 MHz, CDCl₃) 10.82 (s, 1H) 9.03 (s, 1H), 8.64 (s, 2H), 7.77 (d, 1H),7.30 (m, 2H), 6.93 (m, 3H), 6.68 (d, 1H), 6.53 (dd, 1H), 4.88 (s, 2H),4.41 (s, 2H), 3.91 (s, 3H), 3.64 (s, 2H).

Example 3011-(3-Methoxycarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. 1H-NMR(400MHz, CDCl₃) 9.10 (s, 1H), 8.71 (s, 2H), 8.07 (d, 1H), 7.86 (s, 1H),7.50 (t, 1H), 7.30 (m, 3H), 7.07 (s, 1H), 7.01 (t, 2H), 5.05 (s, 2H),4.50 (s, 2H), 3.97 (s, 3H), 3.72 (s, 2H). MS (AP+) 477 (M+H⁺, 25%).

Example 3021-(3-Carboxybenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)-pyrimidin-4-one

Prepared from Example 301 by general method D as colourless crystals.¹H-NMR (400 MHz, DMSO) 13.20 (br s, 1H), 9.07 (s, 1H), 8.78 (s, 2H),8.06 (s, 1H), 7.95 (d, 1H), 7.85 (s, 1H), 7.50 (m, 4H), 7.16 (t, 2H),5.26 (s, 2H), 4.44 (s, 2H), 3.68 (s, 2H).

Example 3031-(3,4-Di-(methoxycarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 106 by general method C2 as a yellow solid. 1H-NMR(250 MHz, CDCl₃) 9.05 (s, 1H), 8.65 (s, 2H), 7.69 (m, 1H), 7.44 (s, 1H),7.27 (m, 3H), 6.96 (m, 3H), 4.99 (s, 2H), 4.62 (s, 2H), 4.09 (s, 6H),3.87 (s, 2H). MS (AP+) 535 (M+H⁺, 100%).

Example 3041-Carboxamidomethyl-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-(pyrid-3-ylmethyl)pyrimidin-4-one

Prepared from Example 70 by general method C1, as a buff powder. MPt147-152° C.; ¹H-NMR (d₆ DMSO) δ 1.2-1.5(8H, m), 1.5-1.8(4H, m), 2.54(2H,t), 3.08(2H, t), 3.56 (2H, s), 4.53(2H, s),7.1-7.9(9H, m), 8.38(1H, m)and 8.48(1H, bs); MS (EI) M=498; C₂₆H₃₁ClN₄O₂S requires 498.

Example 3051-Dimethylaminocarbonylmethyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediates B79 and A1 by general method A4, as a lightbrown crystalline solid. MPt 57-59° C.; ¹H-NMR (CDCl₃) δ 1.37 (6H, m),1.69 (4H, m), 2.92 (2H, t), 3.01 (3H, s), 3.16 (3H, s), 3.68 (2H, s),4.43 (2H, m), 5.06 (2H, s), 7.11 (1H, s), 7.42 (2H, m), 7.89 (2H, m),8.71 (2H, s), 9.11(1H, s).

Example 3061-Carboxamidomethyl-2-benzylthio-5-((2-methoxypyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 88 by general method C1, as a cream solid. MPt126-132° C.; ¹H-NMR (d₆ DMSO) δ 3.53(2H, s), 3.81(3H, s), 4.40(2H, s),4.53), 6.66(1H, s), 6.85(1H, dd), 7.2-7.5(6H, m), 7.63(1H, s), 7.75(1H,bs) and 8.03(1H, d); MS (EI) found M=396; C₂₀H₂₀N₄O₃S requires 396.

Example 3071-(3-(Octadec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.25 (30H, m), 1.47 (2H, m), 2.05 (2H, m), 2.18 (2H, m), 3.21(2H, m), 3.69 (2H, s), 3.92 (2H, m), 4.46 (2H, s), 5.42 (1H, m), 6.98(2H, m), 7.27 (1H, m), 7.37 (2H, m), 8.71 (2H, s), 9.09 (1H, s),MS(APCI⁺) M+1=666, C₃₈H₅₆FN₅O₂S requires 665. MPt 115.1° C. (colourlesssolid).

Example 3081-(3-(Octadec-9-(Z)-en-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.27 (22H, m), 1.47 (2H, m), 1.99-2.20 (8H, m), 3.20 (2H, m),3.69 (2H, s), 3.92 (2H, m), 4.46 (2H, s), 5.32 (2H, m), 5.42 (1H, m),6.99 (2H, m), 7.26 (1H, s), 7.37 (2H, m), 8.71 (2H, s), 9.08 (1H, s),MS(APCI⁺) M+1=664, C₃₈H₅₄FN₅O₂S requires 663 (waxy solid).

Example 3091-(3-(Octadec-9-(E)-en-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.27 (22H, m), 1.47 (2H, m), 1.99-2.20 (8H, m), 3.20 (2H, m),3.69 (2H, s), 3.92 (2H, m), 4.46 (2H, s), 5.37 (2H, m), 5.44 (1H, m),6.99 (2H, m), 7.26 (1H, s), 7.37 (2H, m), 8.71 (2H, s), 9.08 (1H, s),MS(APCI⁺) M+1=664, C₃₈H₅₄FN₅O₂S requires 663. MPt 108.4° C. (colourlesssolid).

Example 3101(3-(N-Dodec-1yl-N-methylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.26 (18H, m), 1.49 (2H, m), 2.02 (2H, m), 2.30 (2H, m), 2.90(3H, s), 3.17, 3.32 (each 1H, m), 3.69 (2H, s), 3.92 (2H, t), 4.46 (2H,s), 6.98 (2H, m), 7.24 (1H, m), 7.35 (2H, m), 8.70 (2H, s), 9.08 (1H,s), MS(APCI⁺) M+1=596, C₃₃H₄₆FN₅O₂S requires 595. MPt 76.9° C.(colourless solid).

Example 3111-(3-(N-Non-1-yl-N-methylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.26 (8H, m), 1.48 (2H, m), 2.05 (2H, m), 2.30 (2H, m), 2.90(3H, s), 3.18, 3.32 (each 1H, m), 3.69 (2H, s), 3.91 (2H, t), 4.46 (2H,s), 6.99 (2H, m), 7.25 (1H, m), 7.35 (2H, m), 8.71 (2H, s), 9.08 (1H,s), MS(APCI⁺) M+1=526, C₂₈H₃₆FN₅O₂S requires 525. (coloured oil).

Example 3121-(4-(Pent-1-ylaminocarbonyl)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 284 by general method E as a solid. ¹H-NMR (CDCl₃)δ 0.82-1.05 (3H, t), 1.21-1.48 (3H, m), 1.52-1.77 (3H, m), 3.38-3.54(2H, q), 3.69(2H, s), 4.49(2H, s), 5.01 (2H, s), 6.14-6.27 (1H, br.t),6.90-7.05 (3H, m), 7.10-7.21 (2H, d), 7.28-7,39(2H, m), 7.70-7.80 (2H,d), 8.65 (2H, s), 9.07 (1H, s); MS (APCI⁺) found (M+1)=532; C₂₉H₃₀FN₅O₂Srequires 531.

Example 3151-(1-(6-(4-Fluorophenyl)hex-1-ylaminocarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 272 by hydrolysis using general method D, followedby amide coupling using general method E. ¹H-NMR (CDCl₃) δ 1.15-1.72(11H, m), 2.47-2.60 (2H, t), 3.17-3.35 (2H, m), 3.52-3.70 (2H, m),4.25-4.49 (2H, br.q), 4.74-4.89 (1H, q), 6.53-6.66 (1H, br.t), 6.87-7.16(6H, m), 7.21-7.40 (2H, m), 7.53 (1H, s), 8.69 (2H, s), 9.08 (1H, s); MS(APCI⁺) found (M+1)=578; C₃₁H₃₃F₂N₅O₂S requires 577.

Example 3161-(3-(11-Dimethylaminoundec-1-ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 1.27(10H, m), 1.47 (4H, m), 1.99-2.20 (4H, m), 2.30 (6H, m), 3.20 (2H, m),3.69 (2H, s), 3.92 (2H, m), 4.46 (2H, s), 5.49 (1H, bm), 6.99 (2H, m),7.26 (1H, s), 7.37 (2H, m), 8.71 (2H, s), 9.08 (1H, s), MS(APCI⁺)M+1=611, C₃₃H₄₇FN₆O₂S requires 610 (gum).

Example 3171-(3-(3-Ethoxyprop-lylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 282 by general method E. ¹H-NMR (CDCl₃) δ1.14-1.35 (5H, m), 1.70-1.88 (2H, m), 2.11-2.23 (2H, t), 3.70-3.43 (2H,q), 3.435-3.60 (4H, m), 3.70 (2H, s), 3.87-4.01 (2H, t), 4.44 (2H, s),6.23-6.38 (1H, br.t), 7.01-7.33 (4H, m), 8.71 (2H, s), 9.09 (1H, s); MS(APCI⁺) found (M+1)=518; C₂₅H₂₉F₂N₅O₃S requires 517.

Example 3181-(3-(5-(Methoxycarbonyl)-5-(benzykloxycarbonylamino)pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 1.2-2.2(10H, m), 3.19 (2H, m), 3.67 (2H, s), 3.74 (3H, s), 3.85 (2H, t), 4.35(1H, m), 4.45 (2H, s), 5.09 (2H, s), 5.55 (2H, m), 6.99 (2H, m),7.22-7.37 (8H, m), 8.71 (2H, s), 9.08 (1H, s), MS(APCI⁺) M+1=691,C35H39FN6O6S requires 690 (colourless foam).

Example 3191-(3-(5-(Methoxycarbonyl)pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 1.2-1.7(6H, m), 1.98-2.21 (4H, m), 2.31 (2H, t), 3.22 (2H, m), 3.66 (3H, s),3.70 (2H, s), 3.92 (2H, t), 4.45 (2H, s), 5.57 (1H, bm), 6.99 (2H, m),7.26 (1H, s), 7.36 (2H, m), 8.71 (2H, s), 9.08 (1H, s); MS(APCI⁺)M+1=542, C₂₇H₃₂FN₅O₄S requires 541. (oil).

Example 3201-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E as a solid. ¹H-NMR (CDCl₃)δ 0.83-0.98 (3H, t), 1.20-1.59 (8H, m), 1.97-2.28 (4H, m), 3.15-3.29(2H, q), 3.69 (2H, s), 3.87-4.01 (2H, t), 4.43 (2H, s), 5.49-5.64 (1H,br.t), 6.99-7.32 (4H, m), 8.71 (2H, s), 9.08 (1H, s); MS (APCI⁺) found(M+1)=516; C₂₆H₃₀F₂N₅O₂S requires 515.

Example 3211-(3-(5-(t-Butoxycarbonylamino)pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 1.18-1.5(15H, m), 2.05 (2H, m), 2.19 (2H, m), 3.16 (4H, m), 3.70 (2H, s), 3.92(2H, t), 4.52 (2H, s), 4.64(1H, bm), 5.71 (1H, bm), 6.99 (2H, m), 7.28(1H, s), 7.37 (2H, m), 8.72 (2H, s), 9.08 (1H, s); MS(APCI⁺) M+1-599,C₃₀H₃₉FN₆O₄S requires 598. (colourless foam).

Example 3221-(3-(6-(t-Butoxycarbonylamino)hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 1.18-1.5(17H, m), 2.04 (2H, m), 2.20 (2H, m), 3.15 (4H, m), 3.69 (2H, s), 3.92(2H, t), 4.45 (2H, s), 4.59 (1H, bm), 5.80 (1H, bm), 6.96 (2H, s), 7.28(1H, s), 7.36 (2H, m), 8.71 (2H, s), 9.08 (1H, s); MS(APCI⁺) M+1=613,C₃₁H₄₁FN₆O₄S requires 612. MPt 90-98° C. (colourless foam).

Example 3231-(3-(Dec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.26 (14H, m), 1.47 (2H, m), 1.98-2.20 (4H, m), 3.20 (2H, m),3.69 (2H, s), 3.92 (2H, t), 4.46 (2H, s), 5.39 (1H, bm), 6.98 (2H, m),7.24 (1H, s), 7.37 (2H, m), 8.70 (2H, s), 9.08 (1H, s); s); MS(APCI⁺)M+1=554, C₃₀H₄₀FN₅O₂S requires 553. MPt 90-98° C. (colorurless solid).

Example 3241-(3-(Dec-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.22 (14H, m), 1.31 (2H, m), 1.87 (2H, m), 2.12 (2H, m), 2.98(2H, m), 3.35 (3H, s), 3.37 (2H, s), 3.84 (2H, m), 4.41 (2H, s), 6.13(2H, m), 7.13 (2H, m), 7.51 (3H, m), 7.77 (2H, m); MS (APCI⁺) M+1=583,C₃₂H₄₃FN₄O₃S requires 582. MPt 133.3° C. (colourless solid).

Example 3251-(3-(Hept-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.27 (8H, m), 1.47 (2H, m), 1.98-2.25 (4H, m), 3.20 (2H, m),3.69 (2H, s), 3.92 (2H, t), 4.52 (2H, s), 5.42 (1H, bm), 6.98 (2H, m),7.25 (1H, s), 7.37 (2H, m), 8.68 (2H, s), 9.08 (1H, s); MS(APCI⁺)M+1=512, C27H34FN5O2S requires 511. MPt 84-89° C. (colourless solid).MPt. 84-89

Example 3261-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.89(3H, m), 1.20-1.55 (8H, m), 1.98-2.20 (4H, m), 3.19 (2H, m), 3.69 (2H,s), 3.92 (2H, t), 4.45 (2H, s), 5.44 (1H, bm), 6.96 (2H, m), 7.25 (1H,s), 7.37 (2H, m), 8.68 (2H, s), 9.08 (1H, s); MS(APCI=)M+1=498,C₂₆H₃₂FN₅O₂S requires 497. MPt 106-109° C. (colourless solid).

Example 3271-(3-(Non-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.87(3H, t), 1.26 (12H, m), 1.47 (2H, m), 1.98-2.25 (4H, m), 3.20 (2H, m),3.69 (2H, s), 3.91 (2H, t), 4.46 (2H, s), 5.39 (1H, bm), 6.98 (2H, m),7.24 (1H, s), 7.37 (2H, m), 8.70 (2H, s), 9.08 (1H, s); MS(APCI⁺)M+1=540, C₂₉H₃₈FN₅O₂S requires 539. MPt 92-97° C. (colourless solid).

Example 3281-(3-(Oct-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.27 (10H, m), 1.47 (2H, m), 1.98-2.20 (4H, m), 3.22 (2H, m),3.69 (2H, s), 3.92 (2H, t), 4.45 (2H, s), 5.43 (1H, bm), 6.98 (2H, m),7.25 (1H, s), 7.37 (2H, m), 8.70 (2H, s), 9.08 (1H, s); MS(APCI⁺)M+1=526, C₂₈H₃₆FN₅O₂S requires 525. MPt 72-83° C. (colourless solid).

Example 3291-(3-(Pent-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 279 by general method E. ¹H-NMR (CDCl₃) δ 0.90(3H, m), 1.17-1.61 (6H, m), 1.98-2.26 (4H, m), 3.20 (2H, m), 3.69 (2H,s), 3.92 (2H, t), 4.45 (2H, s), 5.44 (1H, bm), 6.97 (2H, m), 7.25 (1H,s), 7.38 (2H, m), 8.68 (2H, s), 9.08 (1H, s); MS(APCI⁺) M+1=484,C₂₅H₃₀FN₅O₂S requires 483. MPt 64-69° C. (colourless solid).

Example 3301-(3-(N-Hex-1yl-N-methylaminocarbonyl)prop-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 282 by general method E. ¹H-NMR (CDCl₃) δ0.78-0.99 (3H, m), 1.19-1.77 (8H, m), 1.95-2.14 (2H, m), 2.25-2.44 (2H,q), 2.92 (3H, d), 3.12-3.27 (1H, t), 3.29-3.42 (1H, t), 3.70 (2H, s),3.84-4.00 (2H, t), 4.44 (2H, t), 7.01-7.31 (4H, m), 8.71 (2H, s), 9.10(1H, s); MS (APCI⁺) found (M+1)=530; C₂₇H₃₃F₂N₅O₂S requires 529.

Example 3311-(5-(2-mEthoxyethylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 283 by general method E. ¹H-NMR (CDCl₃) δ1.22-1.85 (6H, m), 2.13-2.25 (2H, t), 3.29-3.38 (3H, s), 3.39-3.53 (4H,s), 3.68-3.85 (4H, m), 4.44 (2H, s), 5.90-6.04 (1H, br.s), 7.01-7.29(4H, m), 8.72 (2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=518;C₂₅H₂₉F₂N₅O₃S requires 517.

Example 3321-(5-(2-Phenylethylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 283 by general method E as a foam. ¹H-NMR (CDCl₃)δ 1.17-1.38 (2H, m), 1.56-1.84 (4H, m), 2.04-2.19 (2H, t), 2.77-2.89(2H, t), 3.41-3.60 (2H, m), 3.64-3.86 (4H, m), 4.43 (2H, s), 5.68-5.85(1H, m), 7.00-7.38 (9H, M), 8.67 (2H, s), 9.06 (1H, s); MS (APCI⁺) found(M+1)=564; C30H31F2N5O2S requires 563.

Example 3331-(5-(But-1-ylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 283 by general method E. ¹H-NMR (CDCl₃) δ0.88-1.00 (3H, t), 1.17-1.76 (10H, m), 2.11-2.22 (2H, t), 3.18-3.30 (2H,q), 3.67-3.88 (4H, m), 4.43 (2H, s), 5.52-5.70 (1H, br.t), 7.00-7.30(4H, m), 8.71 (2H, s), 9.09 (1H, s); MS (APCI⁺) found (M+1)=516;C₂₆H₃₁F₂N₅O₂S requires 515.

Example 334 1-(5-(N-(2-Phenylethyl)-N-methylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 283 by general method E. ¹H-NMR (CDCl₃) δ1.01-1.86 (6H, m), 1.98-2.09 (1H, t), 2.21-2.35 (1H, t), 2.76-2.99 (5H,m), 3.44-3.87 (6H, M), 4.44 (2H, s), 7.00-7.35 (9H, m), 8.71 (2H, d),9.09 (1H, s); MS (APCI⁺) found (M+1)=578; C31H33F2N5O2S requires 577.

Example 3351-(5-(N-But-1-yl-N-methylaminocarbonyl)pent-1-yl)-2-(3,4-difluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 283 by general method E. ¹H-NMR (CDCl₃) δ1.20-1.87 (13H, m), 2.24-2.39 (2H, q), 2.88-2.99 (3H, d), 3.18-3.42 (2H,m), 3.68-3.88 (4H, m) 4.44 (2H, s), 7.00-7.29 (4H, m), 8.72 (2H, s),9.09 (1H, s); MS (APCI⁺) found (M+1)=530; C₂₇H₃₃F₂N₅O₂S requires 529.

Example 3361-((R)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d6 DMSO) δ0.8-0.95 (3H, m), 1.15-1.5 (11H, m), 2.95-3.2 (2H, m), 3.64 (2H, s),4.3-4.5 (3H, m), 4.64 (2H, s), 6.95-7.1 (2H, m), 7.3-7.5 (2H, m), 7.71(1H, d), 8.47 (1H, bd), 8.7 (2H, s), 8.97 (1H, s); MS (APCI⁺) found(M+1)=541; C₂₇H₃₃FN₆O₃S requires 540.

Example 3371-((S)-1-(Hex-1-ylaminocarbonyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d6 DMSO) δ0.8-0.95 (3H, m), 1.2-1.55 (11H, m), 3.0-3.25 (2H, m), 3.64 (2H, s),4.35-4.5 (3H, m), 4.60 (2H, s), 6.90-7.05 (2H, m), 7.25-7.45 (4H, m),8.3 (1H, bd), 8.71 (2H, s), 9.01 (1H, s); MS (APCI⁺) found (M+1)=541;C₂₇H₃₃FN₆O₃S requires 540.

Example 3381-((S)-2-(Hex-1-ylaminocarbonyl)pyrrolidin-1-ylcarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.8-0.95(3H, m), 1.15-1.55 (8H, m), 1.75-2.45 (4H, m), 3.0-3.8 (6H, m), 3.72(2H, bd), 4.35-4.60 (5H, m), 6.43 (1H, m), 6.90-7.05 (2H, m), 7.26 (1H,s), 7.27-7.45 (2H, m), 8.71 (2H, s), 9.09 (1H, s); MS (APCI⁺) found(M+1) 567; C₂₉H₃₅FN₆O₃S requires 566.

Example 3391-(1-Pyrrolidinocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR,(CDCl₃) δ1.87-2.08 (4H, m), 3.44-3.52 (4H, m), 3.72 (2H, s), 4.46 (2H, s), 4.49(2H, s), 6.95 (3H, m), 7.34 (2H, m), 8.73 (2H, s), 9.10 (1H, s); MS(APCI⁺) found (M+1)=440; C₂₂H₂₂FN₅O₂S requires 439.

Example 3401-(3-Butoxyprop-1-ylaminocarbonylmethyl)-2-(4fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.89(3H, t), 1.32 (2H, m), 1.47 (2H, m), 1.75 (2H, m), 3.32-3.44 (4H, m),3.51 (2H, t), 3.71 (2H, s), 4.31 (2H, s), 4.47 (2H, s), 6.73 (1H, br.t),6.98(3H, m), 7,32 (2H, m), 8.71 (2H, s), 9.11 (1H, s); MS (APCI⁺) found(M+1)=500; C₂₅H₃₀FN₅O₃S requires 499.

Example 3411-(6-Hydroxyhex-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃/d6 DMSO) δ1.2-1.6 (8H, m), 3.14 (2H, q), 3.5 (2H, q), 3.67 (2H, s), 3.95 (1H, t)4.44 (2H, s), 4.52 (2H, s), 6.9-7.1 (2H, m), 7.3-7.5 (2H, m), 7.51(1H,s), 8.04 (1H, bt), 8.73 (2H, s), 9.01 (1H, s); MS (APCI⁺) found(M+1)=486; C₂₄H₂₈FN₅O₃S requires 485.

Example 3421-(6-(4-Fluorophenyl)hex-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ1.20-1.55 (8H, m), 2.51 (2H, m), 3.05 (2H, m), 3.59 (2H, s), 4.38 (2H,s), 4.53 (2H, s), 7.03-7.22 (6H, m), 7.43 (2H, m), 7.69 (1H, s), 8.21(1H, m), 8.71 (2H, s), 9.02 (1H, s); MS (APCI⁺) M+1=564, C₃₀H₃₁F₂N₅O₂Srequires 563. MPt 170.8° C. (cream solid). MPt. 170.8

Example 3431-(Tridec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.20 (20H, m), 1.37 (2H, m), 3.06 (2H, m), 3.59 (2H, s), 4.39(2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.44 (2H, m), 7.69 (1H, s), 8.21(1H, m), 8.70 (2H, s), 9.05 (1H, s); MS (APCI⁺) M+1=568, C₃₁H₄₂FN₅O₂Srequires 567. MPt 191.5° C. (colourless solid).

Example 3441-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.23 (2H, m), 1.36 (2H, m), 3.05 (2H, m), 3.59 (2H, s), 4.38(2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.44 (2H, m), 7.69 (1H, s), 8.25(1H, m), 8.70 (2H, s), 9.02 (1H, s); MS (APCI⁺) M+1=582, C₃₂H44FN₅O₂Srequires 581. MPt 191.7° C. (colourless solid).

Example 3451-(Octadec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.87(3H, m), 1.25 (30H, m), 1.47 (2H, m), 3.26 (2H, m), 3.70 (2H, s), 4.37(2H, s), 4.45 (2H, s), 5.95 (1H, m), 6.99 (3H, m), 7.32 (2H, m), 8.70(2H, s), 9.09 (1H, s), MS(APCI⁺) M+1=638, C₃₆H₅₂FN₅O₂S requires 637. MPt189.8° C. (pale yellow solid).

Example 3461-(Octadec-9-(Z)-en-1ylaminocarbonylmethyl)-2-(4-benzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, s), 1.26 (22H, m), 1.47 (2H, m), 2.01 (4H, m), 3.26 (2H, m), 3.71(2H, s), 4.35 (2H, s), 4.46 (2H, s), 5.33 (2H, m), 5.73 (1H, m), 6.98(3H, m), 7.34 (2H, m), 8.70 (2H, s), 9.09 (1H), MS(APCI⁺) M+1=636,C₃₆H₅₀FN₅O₂S requires 635. MPt 179.7° C. (cream solid).

Example 3471-(Octadec-9-(E)-en-1ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, s), 1.26 (22H, m), 1.47 (2H, m), 1.95 (4H, m), 3.26 (2H, m), 3.70(2H, s), 4.36 (2H, s), 4.45 (2H, s), 5.38 (2H, m), 5.87 (1H, m), 6.98(3H, m), 7.32 (2H, m), 8.70 (2H, s), 9.08 (1H, s), MS(APCI⁺) M+1=636,C₃₆H₅₀FN₅O₂S requires 635. MPt 184.6° C. (yellow solid). MPt. 184.6

Example 3481-(Dec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.21 (14H, m), 1.37 (2H, m), 3.06 (2H, m), 3.59 (2H, s), 4.39(2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.42 (2H, m), 7.69 (1H, s), 8.26(1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=526, C₂₈H₃₆FN₅O₂Srequires 525. MPt 187.7° C. (colourless solid). MPt. 187.7

Example 3491-(Dodec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.23 (18H, m), 1.35 (2H, m), 3.05 (2H, m), 3.59 (2H, s), 4.39(2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.43 (2H, m), 7.69 (1H, s), 8.20(1H, m), 8.71 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=554, C₃₀H₄₀FN₅O₂Srequires 553. MPt 191.1° C. (colourless solid).

Example 3501-(Hept-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.84(3H, m), 1.20 (8H, m), 1.37 (2H, m), 3.06 (2H, m), 3.59 (2H, s), 4.38(2H, s), 4.54 (2H, s), 7.13 (2H, m), 7.42 (2H, m), 7.70 (1H, s), 8.26(1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=484, C₂₅H₃₀FN₅O₂Srequires 483. MPt 189.1° C. (colourless solid). 189.1

Example 3511-(Oct-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.25 (10H, m), 1.48 (2H, m), 3.26 (2H, m), 3.70 (2H, s), 4.35(2H, s), 4.46 (2H, s), 5.81 (1H, m), 6.93-7.03 (3H, m), 7.34 (2H, m),8.71 (2H, s), 9.08 (1H, s); MS(APCI⁺) M+1=498, C₂₆H₃₂FN₅O₂S requires497. MPt 191-192° C. (colourless solid). MPt. 190-192

Example 3521-(Undec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from Example 280 by general method E. ¹H-NMR (d6-DMSO) δ 0.85(3H, m), 1.20 (16H, m), 1.37 (2H, m), 3.06 (2H, m), 3.59 (2H, s), 4.39(2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.42 (2H, m), 7.69 (1H, s), 8.26(1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=540. C29H38FN5O2Srequires 539. MPt 190.1° C. (colourless solid). MPt. 190.1

Example 3531-(2-Hydroxyethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E as a white solid ¹H-NMR(d₆ DMSO) δ 3.15 (2H, q), 3.4 (2H, q), 3.58 (2H, s), 4.37 (2H, s), 4.57(2H, s), 4.68 (1H, t), 7.05-7.2 (2H, m), 7.4-7.55 (2H, m), 7.70 (1H, s),8.33 (1H, bt), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) found (M+1)=430;C₂₀H₂₀FN₅O₃S requires 429.

Example 3541-(2-Methoxyethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E as a white solid ¹H-NMR(CDCl₃/d6DMSO) δ 3.2-3.45 (7H, m), 3.63 (2H, s), 4.41 (2H, s), 4.59 (2H,s), 6.95-7.1 (2H, m), 7.35-7.5 (2H, m), 7.69 (1H, s), 8.37 (1H, bt),8.70 (2H, s), 9.06 (1H, s); MS (APCI⁺) found (M+1)=444; C₂₁H₂₂FN₅O₃Srequires 443.

Example 3551-(2-Phenylethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 2.80(2H, t), 3.55 (2H, q), 3.66 (2H, s), 4.32 (2H, s), 4.41 (2H, s), 6.08(1H, bt), 6.9-7.4 (10H, m), 8.66 (2H, s), 9.05 (1H, s); MS (APCI⁺) found(M+1)=490; C₂₆H₂₄FN₅O₂S requires 489.

Example 3561-(2-(4-Pent-1-ylphenyl)ethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.86(3H, m), 1.25 (4H, m), 1.51 (2H, m), 2.46 (2H, m), 2.66 (2H, m), 3.24(2H, m),3.59 (2H, s), 4.39 (2H, s), 4.53 (2H, s), 7.0-7.17 (6H, m), 7.46(2H, m), 7.69 (1H, s), 8.32 (1H, m), 8.71 (2H, s), 9.02 (1H, s); MS(APCI⁺) M+1=560, C₃₁H₃₄FN₅O₂S requires 559. MPt 170.6° C. (colourlesssolid).

Example 3571-(Hex-1-ylaminocarbonylmethylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. white solid ¹H-NMR (d6DMSO) δ 0.8-0.95 (3H, m), 1.2-1.45 (8H, m), 2.95-3.10 (2H, m), 3.58 (2H,s), 3.72 (2H, bd), 4.38 (2H, m), 4.64 (2H, s), 7.05-7.2 (2H, m),7.40-7.55 (2H, m), 7.70 (1H, s), 7.75-7.9 (1H, m), 8.5-8.6 (1H, m), 8.70(2H, s), 9.01 (1H, s); MS (APCI⁺) found (M+1)=527; C₂₆H₃₁FN₆O₃S requires526.

Example 3581-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.25 (18H, m), 1.50 (2H, m), 2.98 (3H, d), 3.21, 3.37 each 1H,m), 3.73 (2H, s), 4.52 (4H, m), 6.88 (1H, s), 6.99 (2H, m), 7.33 (2H,m), 8.71 (2H, s), 9.10 (1H, s), MS(APCI⁺) M+1=568, C₃₁H₄₂FN₅O₂S requires567. MPt 145.3° C. (cream solid).

Example 3591-(N-(2-Phenylethyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E as a solid. ¹H-NMR (CDCl₃)δ 2.78-2.97 (3H, m), 3.05 (2H, s), 3.42-3.57 (1H, m), 3.58-3.69 (2H, m),3.73 (2s), 4.35-4.53 (3H, m), 6.12 (1H, s), 6.90-7.43 (9H, m), 8.62-8.75(2H, d), 9.06-9.18 (1H, d); MS (APCI⁺) found (M+1)=504; C₂₇H₂₆FN₅O₂Srequires 503.

Example 3601-(4-(But-1-ylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 285 by general method E as a solid. ¹H-NMR (CDCl₃)δ 0.85-1.04 (3H, t), 1.20-2.50 (13H, m), 3.18-3.33 (2H, q), 3.70 (2H,s), 4.01-4.20 (1H, m), 4.44 (2H, s), 5.47-5.63 (1H, br.t), 6.93-7.07(2H, t), 7.32-7.43 (2H, m), 7.44 (1H, ), 8.72 (2H, s), 9.08 (1H, s); MS(APCI⁺) found (M+1)=510; C₂₇H₃₂FN₅O₂S requires 509.

Example 3611-(4-(Hex-1-ylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 285 by general method E as a solid. ¹H-NMR (CDCl₃)δ 0.78-0.97 (3H, t), 1.20-2.50 (17H, m), 3.17-3.32 (2H, q), 3.70 (2H,s), 4.03-4.20 (1H, m), 4.44 (2H, s), 5.47-5.60 (1H, br.t), 6.92-7.06(2H, t), 7.30-7.40 (2H, m), 7.44 (1H, s), 8.71(2H, s), 9.09 (1H, s); MS(APCI⁺) found (M+1)=538; C₂₉H₃₆FN₅O₂S requires 537.

Example 3621-(4-(2-Methoxyethylaminocarbonyl)cyclohex-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 285 by general method E as a solid. ¹H-NMR (CDCl₃)δ 1.58-1.90 (4H, m), 2.02-2.30 (4H, m), 2.48 (1H, br.s), 3.36 (3H, s),3.47 (4H, s), 3.64 (2H, s), 4.03-4.20 (1H, m), 4.44 (2H, s), 5.91 (1H,br.s), 6.92-7.06 (2H, t), 7.31-7.45 (3H, m), 8.72 (2H, s), 9.06 (1H, s);MS (APCI⁺) found (M+1)=512; C₂₆H₃₀FN₅O₃S requires 511.

Example 3631-(1-(6-(4-Fluorophenyl)hex-1-yl)aminocarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 269, analogously to Example 315. ¹H-NMR (CDCl₃) δ1.15-1.71 (10H, m), 1.73-1.89 (1H, m), 1.94-2.01 (1H, m), 2.47-2.52 (2H,t), 2.98-3.18 (1H, m), 3.20-3.39 (1H, m), 3.60-3.69 (2H, d), 4.38 (2H,s), 5.64-5.78 (1H, br.t), 6.88-7.01 (4H, m), 7.03-7.20 (3H, m),7.28-7.40 (2H, m), 8.68 (2H, s), 9.07 (1H, s); MS (APCI⁺) found(M+1)=590; C₃₂H₃₃F₂N₅O₂S requires 589.

Example 3641-(1-(Non-1-ylaminocarbonyl)cycloprop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 269, analogously to Example 315. ¹H-NMR (CDCl₃) δ0.78-0.98 (3H, t), 1.11-1.69 (16H, m), 1.73-1.89 (1H, m), 1.95-2.11 (1H,m), 3.00-3.19 (1H, m), 3.22-3.41 (1H, m), 3.55-3.78 (2H, br.q), 4.40(2H, s), 5.52-5.65 (1H, br.t), 6.92 7.07 (2H, t), 7.26 (1H, s),7.29-7.40 (2H, m), 8.69 (2H, s), 9.09 (1H, s); MS (APCI⁺) found(M+1)=538; C₂₉H₃₆FN₅O₂S requires 537.

Example 3651-((R)-1-(Non-1-ylaminocarbonyl)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 272, analogously to Example 315. ¹H-NMR (CDCl₃) δ0.80-0.94 (3H, t), 1.15-1.37 (12H, m), 1.38-1.54 (2H, m), 1.55-1.66 (3H,d), 3.10-3.36 (2H, m), 3.58-3.80 (2H, br.q), 4.32-4.55 (2H, br.q),4.72-4.88 (1H, q), 6.08-6.20 (1H, br.t), 6.41-7.06 (2H, t), 7.29-7.39(2H, m), 7.50 (1H, s), 8.70 (2H, s), 9.07 (1H, s); MS (APCI⁺) found(M+1)=526; C₂₈H₃₆FN₅O₂S requires 525.

Example 3661-(11-(Dimethylamino)undec-1-ylaminocarbonylmethyl)-2-(4-fluorophorobenzyl)thio-5(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 1.20(16H, m), 1.37 (2H, m), 2.15 (6H, s), 2.22 (2H, m), 3.07 (2H, m), 3.59(2H, s), 4.38 (2H, s), 4.54 (2H, s), 7.13 (2H, m), 7.43 (2H, m), 7.70(1H, s), 8.26 (1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=583,C₃₁H₄₃FN₆O₂S requires 582. MPt 152-155° C. (colourless solid). MPt.152-155

Example 3671-(2-(6-(4-Fluorophenyl)hex-1-yloxy)ethylaminocabonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 1.26(4H, m), 1.47 (4H, m), 2.56 (2H, m), 3.23 (2H, m), 3.40 (4H, m), 3.59(2H, s), 4.38 (2H, s), 4.56 (2H, s), 7.03-7.21 (6H, m), 7.43 (2H, m),7.69 (1H, s), 8.26 (1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺)M+1=608, C₃₂H₃₅F₂N₅O₃S requires 607. MPt 155-159° C. (colourless solid).MPt. 155-159

Example 3681-(5-(Methoxycarbonyl)-5-(benzyloxycarbonylamino)pent-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 1.35(4H, m), 1.61 (2H, m), 3.05 (2H, m), 3.61 (5H, m), 3.99 (1H, m), 4.38(2H, s), 4.52 (2H, s), 5.03 (2H, s), 7.11 (2H, m), 7.34 (5H, m), 7.44(2H, m), 7.69 (2H, m), 8.24 (1H, m), 8.71 (2H, s), 9.02 (1H, s); MS(APCI⁺) M+1=663, C₃₃H₃₅FN₆O₆S requires 662. (colourless solid).

Example 3691-(5-(Methoxycarbonyl)pent-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ1.19-1.55 (6H, m), 2.24 (2H, m), 3.06 (2H, m), 3.58 (3H, s), 3.60 (2H,s), 4.39 (2H, s), 4.53 (2H, s), 7.12 (2H, m), 7.44 (2H, m), 7.69 (1H,s), 8.26 (1H, m), 8.70 (2H, s), 9.03 (1H, s); MS (APCI⁺) M+1=514,C₂₅H₂₈FN₅O₄S requires 513. MPt 166.8° C. (colourless solid). MPt.166-172

Example 3701-(Non-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 0.85(3H, m), 1.21 (12H, bs), 1.35 (2H, m), 3.07 (2H, m), 3.60 (2H, s), 4.39(2H, s), 4.53 (2H, s), 7.14 (2H, m), 7.45 (2H, m), 7.69 (1H, s), 8.22(1H, m), 8.68 (2H, s), 9.06 (1H, s); MS (APCI⁺) M+1=512, C₂₇H₃₄FN₅O₂Srequires 511. MPt 200-202° C. (colourless solid).

Example 3711-Dimethylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E as a solid. ¹H-NMR (DMSO)δ 2.86 (3H, s), 2.97 (3H, s), 3.59 (2H, s), 4.39 (2H, s), 4.86 (2H, s),7.06-7.20 (2H, t), 7,49-7.52 (2H, m), 7.59 (1H, s), 8.70 (2H, s), 9.04(1H, s); MS (APCI⁺) found (M+1)=414; C₂₀H₂₀FN₅O₂S requires 413.

Example 3721-(N-(2-Hydroxyethyl)-N-methylaminocabonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. pale yellow solid ¹H-NMR(d6 DMSO) δ 2.86+3.02 (2H, 2×s), 3.2-3.65 (6H, m), 4.39 (2H, s),4.6-5.05 (3H, m), 7.05-7.2 (2H, m), 7.35-7.55 (2H, m), 8.70 (2H, s),9.03 (1H, s); MS (APCI⁺) found (M+1)=444; C₂₁H₂₂FN₅O₃S requires 443.

Example 3731-(trans-4-(4-Fluorobenzylaminocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 273, analogously to Example 315. ¹H-NMR (CDCl₃) δ0.80-2.15 (10H, m), 3.51-3.65 (2H, d), 3.71 (2H, s), 4.33-4.43 (2H, d),4.47 (2H, s), 5.64-5.78 (1H, br.t), 6.89 (1H, s), 6.92-7.08 (4H, t),7.15-7.44 (4H, m), 8.69 (2H, s), 9.10 (1H, s); MS (APCI⁺) found(M+1)=576; C₃₁H₃₁F₂N₅O₂S requires 575.

Example 3741-(trans4-(Pent-1-ylaminocarbonyl)cyclohex-1-ylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 273, analogously to Example 315. ¹H-NMR (CDCl₃) δ0.81-2.09 (19H, m), 3.16-3.40 (2H, q), 3.52-3.65 (2H, d), 3.71 (2H, s),4.46 (2H, s), 5.32-5.45 (1H, br.t), 6.89 (1H, s), 6.95-7.08 (2H, t),7.30-7.45 (2H, m), 8.70 (2H, s), 9.11 (1H, s); MS (APCI⁺) found(M+1)=538; C₂₉H₃₆FN₅O₂S requires 537.

Example 3751-(3-(Hex-1ylaminocarbonyl)prop-1-yl)-2-(4-fluorobenzyl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one

Prepared from Example 281 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, t), 1.28 (6H, m), 1.45 (2H, m), 2.04 (2H, m), 2.20 (2H, m), 3.19(2H, m), 3.50 (3H, s), 3.54 (2H, s), 3.86 (2H, t), 4.47 (2H, s), 5.69 (1h, bm), 6.21 (1H, m), 6.34 (1H, s), 7.01 (2H, m), 7.09 (1H, s), 7.19(1H, d), 7.39 (2H, ml): MS (APCI⁺) M+1=527, C₂₈H₃₅FN₄O₃S requires 526.MPt 134-136° C. (colourless solid). MPt. 134-136

Example 3761-(N-(N′-Hex-1-yl-N′-methylaminocarbonylmethyl)-N-methyl-aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimidyl-5-ylmethylopyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.28 (6H, m), 1.4-1.65 (2H, m), 2.92-3.09 (6H, m), 3.17-3.36(2H, m), 3.70 (2H, s), 4.05-4.19 (2H, m), 4.48-4.67 (4H, m), 6.97 (2H,m) 7.07 (1H, s), 7.35 (2H, m), 8.71 (2H, s), 9.08 (1H, s); MS (APCI+)found (M+1)=555; C₂₈H₃₅FN₆O₃S requires 554.

Example 3771-(N-(N′-Hex-1-ylaminocarbonylmethyl)-N-methylaminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.87(3H, m), 1.26 (6H, m), 1.44 (2H, m), 2.98 and 3.14 (3H, 2Xs), 3.19 (2H,m), 3.70 (2H, s), 3.87 and 3.97 (2H, 2Xs), 4.46 (2H, m), 4.64 (2H, m),5.98 and 6.16 (1H, 2Xt), 6.98 (3H, m), 7.33 (2H, m), 8.70 (2H, s), 9.08(1H, s); MS (APCI+) found (M+1)=541; C₂₇H₃₃FN₆O₃S requires 554.

Example 3781-(N-(N′-Hex-1-yl-N′-methylaminocarbonylmethyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 0.88(3H, m), 1.28 (6H, m), 1.52 (2H, m), 2.94 (3H, m), 3.18 and 3.38 (2H,2Xt), 3.72 (2H, s), 4.03 (2H, m), 4.47 (4H, m), 6.98 (3H, m), 7.34 (2H,m), 8.71 (2H, s), 9.09 (1H, s); MS (APCI+) found (M+1)=541; C₂₇H₃₃FN₆O₃Srequires 540.

Example 3791-Phenylaminocarbonylmethyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 3.62(2H, s), 4.41 (2H, s), 4.79 (2H, s), 7.0-7.2 (3H, m), 7.25-7.4 (2H, m),7.4-7.6 (4H, m), 7.76 (1H, bs), 8.72 (2H, s), 9.04 (1H, s); MS (APCI+)found (M+1 )=462; C₂₄H₂₀FN₅O₂S requires 461.

Example 3801-(4-Methoxycarbonylbenzylaminocarbonylmethyl)-2(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (d₆-DMSO) δ 3.60(2H, s), 3.86 (3H, s), 4.38 (2H, s), 4.40 (2H, s), 4.67 (2H, s),7.05-7.25 (2H, m), 7.3-7.55 (4H, m), 7.74 (1H, s), 7.84 (2H, d), 8.70(2H, s), 8.93 (1H, t), 9.03 (1H, s); MS (APCI+) found (M+1))=532;C₂₇H₂₄FN₅O₄S requires 533.

Example 3811-(N-Benzylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl₃) δ 3.66(2H,s), 4.41(4H, s), 4.45(2H, d, j=5.7 Hz), 6.40(1H, brs), 6.94(1H, t, j=8.6Hz), 7.03(1H, s), 7.23(8H, m), 8.66(2H, s), 9.06(1H, s): MS (APCI) found(M+H )=476; C₂₅H₂₂FN₅O₂S requires 475.

Example 3821-(N,N-Di-(but-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 280 by general method E. ¹H-NMR (CDCl3) δ 0.8-1.05(6H, m), 1.1-1.75 (8H, m), 3.19 (2H, t), 3.33 (2H, t), 3.72 (2H, s),4.49 (2H, s), 4.52 (2H, s), 6.85-7.1 (3H, m), 7.3-7.45 (2H, m), 8.70(1H, s), 9.09 (1H, s); MS (APCI+) found (M+1)=498; C₂₈H₃₂FN₅O₂S requires497

Example 3831-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 108 by general method C2. ¹H-NMR (CDCl₃) δ 0.85(3H, t), 1.2 (18H, m), 1.5 (2H, m,), 2.92 and 2.95 (3H, 2×s), 3.17 and3.33 (2H, 2xs), 3.63 (2H, s), 3.96 (3H, s), 4.45 (2H, s), 4.49 and 4.52(2H, 2×s), 6.79 (1H, s), 6.95 (2H, m), 7.30 (2H, m), 8.42 (2H, s); MS(APCI+) found (M+1)=598, C₃₂H₄₄FN₅O₃S requires 597.

Example 3841-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 108 by general method C2. ¹H-NMR (CDCl₃) δ0.8-0.95 (3H, m), 1.1-1.7 (12H, m), 2.95 and 2.99 (3H, 2xs), 3.21 and3.36 (2H, 2xt), 3.66 (2H, s), 3.99 (3H, s), 4.48 (2H, s), 4.51 and 4.55(2H, d), 6.80 (1H, s), 6.9-7.1 (2H, m), 7.3-7.45 (2H, m), 8.45 (2H, s);MS (APCI+) found (M+1)=542; C₂₈H₃₆FN₅O₃S requires 541.

Example 3851-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-etboxypyrimid-5-ylmethyl)pyrimidin-4-one

Isolated as an impurity from one of the batches of Example 384, whichhad in turn been made from an impure batch of Example 108. ¹H-NMR(CDCl₃) δ 0.8-0.95 (3H, t), 1.1-1.7 (12H, m), 1.42 (3H, t), 2.95 and2.99 (3H, 2xs), 3.23 and 3.36 (2H, 2xt), 3.65 (2H, s), 4.39 (2H, q),4.49 (2H, s), 4.50 and 4.54 (2H, d), 6.77 (1H, s), 6.9-7.1 (2H, m),7.3-7.4 (2H, m), 8.43 (2H, s); MS (APCI+) found (M+1)=556; C₂₉H₃₈FN₅O₃Srequires 555.

Example 3861-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-benzyloxypyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 109 by general method C2. ¹H-NMR (CDCl₃) δ0.75-1.0 (3H, t), 1.05-1.75 (12H, m), 2.95 and 2.98 (3H, 2xs), 3.20 and3.36 (2H, 2xs), 3.65 (2H, s), 4.4-4.6 (4H, m), 5.42 (2H, s), 6.80 (1H,s), 6.9-7.1 (2H, m), 7.05-7.2 (2H, m), 7.15-7.55 (7H, m), 8.45 (2H, s);MS (APCI−) found (M+1)=618; C₃₄H₄₀FN₅O₃S requires 617.

Example 3871-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

To a stirring solution of Example 383 (7.05 g) in dichloromethane (200ml) was added in one portion B-bromocatecholborane (10 g). Afterstirring for 16 h at room temperature, the mixture was poured into waterwith stirring, diluted with more dichloromethane, shaken, and the phasesallowed to separate slowly. The organic layer was purified by flashchromatography (silica, methanol-dichloromethane) and trituration withpet. ether. ¹H-NMR (CDCl₃) δ 0.87 (3H, m), 1.2-1.4 (20, m), 2.88 and2.96 (3H, 2xs), 3.15-3.4 (4H, m), 3.43 (2H, s), 4.41 (2H, m), 4.88 (2H,m), 6.9-7.0 (2H, m), 7.25-7.4 (2H, m), 7.50 (1H, m), 8.15 (2H, b); MS(APCI+) found (M+1)=584; C₃₁H₄₂FN₅O₃S requires 583.

Example 3881-(N-Methyl-N-(oct-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-ylmethyl)pyrimidin-4-one

Prepared analogously to Example 387, from Example 384. 1H-NMR (d₆ DMSO)δ 0.8-0.95 (3H, m), 1.05-1.65 (12, m), 2.81 and 2.94 (3H, 2xs), 3.15-3.4(4H, m), 4.39 (2H, s), 4.83 and 4.85 (2H, 2xd), 7.05-7.2 (2H, m),7.35-7.55 (3H, m), 7.95-8.35 (2H, b); MS (APCI+) found (M+1)=526.C₂₇H₃₅FN₅O₃S requires 525.

Example 3891-(3-(N-(Hept-1-yl)-N-methylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4one

Prepared from Example 288 by general method E. 1H NMR (DMSO-d6) δ:0.7-1.05 (m, 6H), 1.3 (m, 5H), 1.41 (m, 1H), 1.56 (br s, 1H), 2.9 (d,3H), 3.15 (m, 1H), 3.4 (m, 1H), 3.63 (s, 2H), 4.30 (s, 2H), 7.10 (t,2H), 7.41 (m, 2H), 7.55 (m, 1H), 7.60-7.85 (m, 3H), 7.95 (m, 1H), 8.78(s, 2H), 9.02 (s, 1H). MS (APCI+) Found (M+1) 560; C₃₁H₃₄FN₅O₂S requires559.

Example 3901-(3-(N-Ethyl-N-methylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 288 by general method E. ¹H NMR (DMSO-d₆) δ:1.0-1.2 (m, 3H), 2.9 (d, 3H), 3.18 (m, 1H), 3.45 (m, 1H), 3.62 (s, 2H),4.31 (s, 2H), 7.10 (t, 2H), 7.40 (m, 2H), 7.60-7.85 (m, 4H), 7.96 (s,1H), 8.78 (s, 2H), 9.01 (s, 1H). MS (APCI+) Found (M+1)=490;C₂₆H₂₄FN₅O₂S requires 489.

Example 3911-(4-(Prop-1-ylaminocarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 292 by general method E. ¹H NMR (CDCl₃) δ: 1.00(t, 3H), 1.65 (m, 2H), 3.44 (q, 2H), 3.81 (s, 2H), 4.35 (s, 2H), 6.15(t, 1H), 6.95 (t, 2H), 7.20 (s, 1H), 7.25 (m, 2H), 7.41 (d, 2H), 7.89(d, 2H), 8.95 (s, 2H), 9.20 (s, 1H). MS (APCI+) Found (M+1)=490;C₂₆H₂₄FN₅O₂S requires 489.

Example 3921-(4-(But-1-ylaminocarbonyl)phenyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 293 by general method E. ¹H NMR (CDCl₃) δ: 1.01(t, 3H), 1.21 (m, 2H), 1.3 (m, 6H), 1.7 (m, 4H), 2.91 (t, 2H), 3.15 (t,2H), 3.46 (m, 2H), 3.73 (s, 2H), 6.29 (t, 1H), 7.03 (s, 1H), 7.4 (m,4H), 7.95 (m, 4H), 8.71 (s, 2H), 9.08 (s, 1H). MS (APCI+) Found(M+1)=618/620; C₃₃H₃₆ClN₅O₃S requires 618.

Example 3931-(4-(Hex-1-yloxycarbonyl)phenyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 292 by general method E as a white solid, m.p.121-123. ¹H NMR (CDCl₃) δ: 0.89 (t, 3H), 1.35 (m, 4H), 1.65 (m, 4H),3.46 (q, 2H), 3.74 (s, 2H), 4.36 (s, 2H), 6.11 (t, 1H), 6.95 (t, 2H),7.04 (s, 1H), 7.30 (m, 2H), 7.39 (d, 2H), 7.90 (d, 2H), 8.72 (s, 2H),9.10 (s, 1H). MS (APCI+) Found (M+1)=532; C₂₉H₃₀FN₅O₂S requires 531.

Example 3941-(4-Methylaminocarbonylbenzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Carbonyl diimidazole (105 mg, 0.65 mmol) was added to a suspension ofExample 284 (150 mg, 0.32 mmol) in dichloromethane (10 ml) under anatmosphere of argon and the reaction stirred for 1 h. Methylamine (1.62ml, 2M solution in THF) was added and stirring continued for 2 h. Thesolvent was removed under reduced pressure and the residue partitionedbetween ethyl acetate and water. The aqueous phase was extracted withethyl acetate and the combined organic phase dried (MgSO₄) and the thesolvent removed under reduced pressure. The residue was purified byflash chromatography (10% methanol/ethyl acetate) to afford the desiredcompound as an off white solid (77 mg, 50%).

¹H-NMR (CDCl₃) 8.90 (s, 1H), 8.47 (s, 2H), 7.60 (m, 2H), 7.25-6.65 (m,6H), 6.28 (s, 1H), 4.85 (s, 2H), 4.27 (s, 2H), 3.51 (s, 2H), 2.85 (s,3H). MS (AP+) 476 (M+H⁺,100%).

Example 3951-(3-Methylaminocarbonyl-4-(hept-1-yloxy)benzyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared analogously to Example 394, from Example 298, as an off whitesolid. 1H-NMR (CDCl₃) 8.98 (s, 1H), 8.67 (s. 2H), 8.58 (s, 1H), 8.06 (m,1H), 7.28 (m, 2H), 7.06 (m, 2H), 6.89 (m, 2H), 4.87 (s, 2H), 4.38 (s,2H), 4.05 (t, 2H), 3.58 (s, 2H), 2.93 (s, 3H), 1.81 (m, 2H), 1.45-1.15(m, 8H), 0.82 (m, 3H). MS (AP+) 590 (M+H⁺, 100%).

Example 3961-(2-(t-Butoxycarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B138 by general method A2. ¹H-NMR (CDCl₃) δ1.41 (9H, s), 3.43 (2H, q, J 6.0 Hz), 3.67 (2H, s), 3.97 (2H, s), 4.46(2H, s), 4.88 (1H, s), 6.99 (2H, m), 7.07 (1H, s), 7.36 (2H, m), 8.70(2H, s) and 9.09 (1H, s). (APCI⁺) Found (M+1)=472. C₂₃H₂₆FN₅O₃S requires471.

Example 3971-(2-(Trifluoroacetylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

The compound of Example 396 (200 mg) was dissolved in neat TFA (1 ml) atroom temperature. After 5 min. the solution was concentrated to a browngum and re-evaporated from ethyl acetate. The crude amine salt in ethylacetate (5 ml) was treated with diisopropylethylamine (81 mg) and acetylchloride (50 mg) for 24 h. The crude reaction mixture was purified bysilica gel chromatography to give the title compound as a colourlesssolid, (72 mg, 37%), ¹H-NMR (CDCl₃) δ 3.58 (2H, s), 3.77 (2H, m), 4.11(2H, t, J 4.7 Hz), 4.37 (2H, s), 6.92-7.02 (3H, m), 7.24-7.31 (2H, m),8.63 (2H, s), 9.04 (1H, s) and 9.13 (1H, t, J 5.5 Hz). (APCI−) Found(M−1)=466. C₂₀H₁₇F₄N₅O₂S requires 467.

Example 3981-(2-(Benzoylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

The compound of Example 396 was treated with trifluoroacetic acid asdescribed in the previous example. A solution of the salt in ethylacetate was treated with excess 1M hydrochloric acid in ether. Thecorresponding dihydrochloride salt was precipitated, filtered, washedwith ether and dried in vacuo to give the crude salt as a white solid.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg),1-hydroxy-benzotriazole hydrate (52 mg) and benzoic acid (42 mg) indichloromethane (5 ml) at room temperature was treated with the abovedihydrochloride (150 mg). Diisopropylethylamine (88 mg) in DMF (1 ml)was added and the solution stirred for 48 h. The reaction mixture wasdiluted with dichloromethane washed with water, brine, dried overanhydrous magnesium sulfate and concentrated. The crude product waspurified by silica gel chromatography to give the title compound as awhite solid, (84 mg, 52%), ¹H-NMR (CDCl₃) 3.52 (2H, s), 3.60 (2H, m),4.04 (2H, t, J 5.5 Hz), 4.36 (2H, s), 7.09 (2H, m), 7.35-7.53 (5H, m),7.71-7.75 (3H, m), 8.63 (3H, m and s) and 9.02 (1H, s). (APCI⁺) Found(M+1)=476. C₂₅H₂₂FN₅O₂S requires 475.

Example 3991-(2-(Hex-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared analogously to Example 398, using heptanoic acid. 1H-NMR(CDCl₃) δ 0.87 (3H, t, J 6.8 Hz), 1.26 (6H, br.s), 1.56 (2H, m), 2.14(2H, t, J 7.9 Hz), 3.54 (2H, dd, J 5.8, 5.9 Hz), 3.66 (2H, s), 4.00 (2H,t, J 5.9 Hz), 4.43 (2H, s), 6.19 (1H, t, J 5.8 Hz) 7.02 (2H, m), 7.06(1H, s), 8.70 (2H, s) and 9.08 (1H, s). (APCI⁺) Found (M+1)=484.C₂₅H₃₀FN₅O₂S requires 483.

Example 4001-(2-(5-Phenylpent-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

a) Prepared analogously to Example 398, using 6-phenylhexanoic acid.1H-NMR (CDCl₃) δ 1.33 (2H, m), 1.61 (4H, m), 2.13 (2H, t, J 7.7 Hz),2.59 (2H, t, J 7.7 Hz), 3.52 (2H, m), 3.60 (2H, s), 3.97 (2H, t, J 5.8Hz), 4.40 (2H, s), 6.44 (1H, t, J 5.2 Hz), 6.99 (2H, t, J 8.6 Hz), 7.04(1H, s), 7.12-8.57 (7H, m), 8.67 (2H, s) and 9.05 (1H, s). (APCI⁺) Found(M+1)=546. C₃₀H₃₂FN₅O₂S requires 545.

b) Also prepared by reaction of the amine dihydrochloride with6-phenylhexanoyl chloride in the presence of diisopropylarnine. Afterwork up and purification by silica gel chromatography, the titlecompound was obtained as a colourless solid in 49% yield.

Example 4011-(2-(Hept-1-ylcarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared analogously to Example 398, using octanoic acid. 1H-NMR (CDCl₃)δ 0.86 (3H, t, J 6.8 Hz), 1.25 (8H, br.s), 1.58 (2H, m), 2.16 (2H, t, J7.8 Hz), 3.55 (2H, m), 3.63 (2H, s), 4.01 (2H, t, J 5.7 Hz), 4.40 (2H,s), 6.69 (1H, br.t, J 5.4 Hz), 6.98 (2H, t, J 8.5 Hz), 7.09 (1H, s),7.31 (2H, m), 8.69 (2H, s) and 9.07 (1H, s). (APCI⁺) Found (M+1)=498.C₂₆H₃₂FN₅O₂S requires 497.

Example 4021-(2-Acetylaminoethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-pyrimid-5-ylmethylpyrimidin-4-one

Prepared from intermediate B76 by general method A4. ¹H-NMR (CDCl₃) δ1.2-1.9(10H, m), 2.02(3H, s), 2.92(2H, t), 3.20(2H, t), 3.5-3.8(4H, m),4.04(2H, m), 7.04(1H, s), 7.43(2H, m), 7.88(2H, m), 8.71(2H, s) and9.06(1H, s); MS (APCI+) found (M+1)=542; C₂₇H₃₂ClN₅O₃S requires 541.

Example 4031-(4-(tert-Butoxycarbonylamino)but-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B122 by general method A2. ¹H NMR (CDCl₃) δ:1.43 (s, 9H), 1.5 (m, 2H), 1.75 (m, 2H), 3.15 (m, 2H), 3.70 (s, 2H),3.83 (t, 2H), 4.46 (s, 2H), 4.65 (br s, 1H), 7.00 (t, 2H), 7.20 (s, 1H),7.37 (m, 2H), 8.70 (s, 2H), 9.08 (s, 1H). MS (APCI+) Found (M+1)=500;C₂₅H₃₀FN₅O₃S requires 499.

Example 4041-(3-(Ethoxycarbonylamino)prop-1-yl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from intermediate B123 by general method A2. ¹H NMR (CDCl₃) δ:1.23 (t, 3H), 1.93 (m, 2H), 3.20 (q, 2H), 3.71 (s, 2H), 3.86 (t, 2H),4.10 (m, 2H), 4.46 (s, 2H), 5.25 (br s, 1H), 7.00 (t, 2H), 7.30 (s, 1H),7.40 (m, 2H), 8.72 (s, 2H), 9.06 (s, 1H). MS (APCI+) Found (M+1)=458;C₂₂H₂₄FN₅O₃S requires 457.

Example 4051-(2-(Benzylaminocarbonyiamino)ethyl)-2-(4-fluorobenzyl)thio-5-pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 3.39(2H, s), 3.58 (2H, m), 4.03 (2H, t, J 5.7 Hz), 4.31 (2H, s), 4.30 (2H,d, J 5.0 Hz), 5.97 (1H, t, J 5.9 Hz), 6.26 (1H, t, J 5.6 Hz), 6.91-6.99(3H, m), 7.20-8.58 (7H, m), 8.58 (2H, s) and 9,05 (1H, s). (APCI⁺) Found(M+1)=505. C₂₆H₂₅FN₆O₂S requires 504.

Example 4061-(2-(Dodec-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 0.87(3H, t, J 6.8 Hz), 1.27 (18H, v.br s), 1.48 (2H, m), 3.17 (2H, dd, J6.5, 13.0 Hz), 3.52 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J 5.0 Hz), 4.40(2H, s), 5.21 (1H, m), 5.70 (1H, m), 6.95 (2H, m), 7.10 (1H, s), 7.30(2H, m), 8.66 (2H, s) and 9.08 (1H, s). (APCI⁺) Found (M+1)=583.C₃₁H₄₃FN₆O₂S requires 582.

Example 4071-(2-(Hept-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 0.85(3H, m), 1.26 (8H, m), 1.49 (2H, m), 3.16 (2H, m), 3.51-3.60 (4H, s andm), 4.04 (2H, t, J 5.8 Hz), 4.39 (2H, s), 5.30 (1H, m), 5.83 (1H, m),6.94-7.02 (2H, m), 7.07 (1H, s), 7.28-8.60 (2H, m), 8.67 (2H, s) and9.08 (1H, s). (APCI⁺) Found (M+1)=513. C₂₆H₃₃FN₆O₂S requires 512.

Example 4081-(2-(Oct-1-ylaminocarbonyamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 0.86(3H, m), 1.24 (10H, m), 1.50 (2H, m), 3.17 (2H, dd, J 6.8, 13.0 Hz),3.52 (2H, m), 3.57 (2H, s), 4.04 (2H, t, J 5.5 Hz), 4.39 (2H, s), 5.31(1H, m), 5.85 (1H, m), 7.01 (2H, m), 7.07 (1H, s), 7.30 (2H, m), 7.68(2H, s) and 9.08 (1H, s). (APCI⁺) Found (M+1)527. C₂₇H₃₅FN₆O₂S requires526.

Example 4091-(2-(2-Thien-2-ylethylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 3.06(2H, t, J 6.8 Hz), 3.52 (6H, m), 4.01 (2H, t, J 5.6 Hz), 4.37 (2H, s),5.47 (1H, t, J 5.7 Hz), 5.97 (1H, t, J 5.3 Hz), 6.85-7.31 (8H, m), 8.65(2H, s) and 9.07 (1H, s). (APCI⁺) Found (M+1)=525. C₂₅H₂₅FN₆O₂S₂requires 524.

Example 4101-(2-(1,1,3,3-Tetramethylbut-1-ylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 1.01(9H, s), 1.39 (6H, s), 1.75 (2H, s), 3.51 (2H, m), 3.59 (2H, s), 4.02(2H, t, J 5.5 Hz), 4.39 (2H, s), 5.25 (1H, s), 5.78 (1H, t, J 5.6 Hz),6.98 (2H, m), 7.13 (1H, s), 7.31 (2H, m), 8.67 (2H, s) and 9.08 (1H, s).(APCI⁺) Found (M+1)=527. C₂₇H₃₅FN₆O₂S requires 526.

Example 4111-(2-(4-(Butoxycarbonyl)phenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 0.97(3H, t, J 7.4 Hz), 1.44 (2H, m), 1.73 (2H, m), 3.54 (2H, s), 3.67 (2H,m), 4.13 (2H, m), 4.28 (4H, m), 6.92 (3H, m), 7.18 (2H, m), 7.55 (2H, d,J 8.8 Hz), 7.93 (2H, d, J 8.8 Hz), 8.62 (2H, s), 8.82 (1H, s) and 9.10(1H, s). (APCI⁺) Found (M+1)=591. C₃₀H₃₁FN₆O₄S requires 590.

Example 4121-(2-(4-(1-Methylethyl)phenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 1.20(6H, d, J 6.9 Hz), 2.84 (1H, m), 3.55 (2H, s), 3.60 (2H, m), 4.12 (2H,t, J 4.8 Hz), 4.33 (2H, s), 6.48 (1H, m), 6.92 (2H, m), 7.11-7.34 (7H,m), 8.00 (1H, s), 8.63 (2H, s) and 9.10 (1H, s). (APCI⁺) Found(M+1)=533. C₂₈H₂₉FN₆O₂S requires 532.

Example 4131-(2-(4-Methylphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 2.29(3H, s), 3.54 (2H, s), 3.60 (2H, m), 4.11 (2H, t J 5.5 Hz), 4.32 (2H,s), 6.50 (1H, m), 6.90-7.08 (4H, m), 7.18-7.30 (5H, m), 8.03 (1H, br.s),8.64 (2H, s) and 9.09 (1H, s). (APCI⁺) Found (M+1)=5.05. C26H25FN6O2Srequires 504.

Example 4141-(2-(4-Ethoxyphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. 1H-NMR (CDCl₃) δ 1.40(3H, t, J 4.2 Hz), 3.57 (4H, v.br.s), 3.97 (2H, q, J 4.2 Hz), 4.08 (2H,t, J 5.4 Hz), 4.34 (2H, s), 6.13 (1H, br.s), 6.79-6.98 (4H, m), 7.17(1H, s), 7.23 (4H, m), 7.63 (1H, br.s), 8.66 (2H, s) and 9.09 (1H, s).(APCI⁺) Found (M+1)=535. C₂₇H₂₇FN₆O₃S requires 534.

Example 4151-(2-(4-Phenoxyphenylaminocarbonylamino)ethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one

Prepared from Example 396 by general method F. ¹H-NMR (CDCl3) δ 3.56(2H, s), 3.63 (2H, m), 4.13 (2H, m), 6.57 (1H, m), 6.57-8.22 (14H, m),8.23 (1H, s), 8.65 (2H, s) and 9.05 (1H, s). (APCI⁺) Found (M+1)=583.C₃₁H₂₇FN₆O₃S requires 582.

REFERENCES

1. EP 645370 (1995)

2. Eur J Med Chem 1989, 24 (1), 65

3. Eur J Med Chem 1990, 25 (3), 217

4. Eur J Med Chem 1993, 28 (7-8), 601

5. J Labelled Comp Radiopharn 1987, 24 (4), 431

6. J Med Chem 1995, 38, 3850

7. EP 117345 (1984)

8. EP 68833 (1982)

9. Liebigs Ann Chem 1994, 1849

10. J Amer Chem Soc 1950, 72, 3539

11. GB 1 582 527

12. Bull. Soc. Chi. Fr. 1263 (1956); ibid. 1466 (1957)

13. DE 84-3414752 A11984

14. Tet Lett 1983, 24(48), 5309-5312

15. J. Chem. Soc. 1957, 3314.

Biological Data

1. Screen for Lp-PLA₂ inhibition.

Enzyme activity was determined by measuring the rate of turnover of theartificial substrate (A) at 37 C. in 50 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing150 mM NaC1, pH 7.4.

Assays were performed in 96 well titre plates. Recombinant LpPLA₂ waspurified to homogeneity from baculovirus infected Sf9 cells, using azinc chelating column, blue sepharose affinity chromatography and ananion exchange column. Following purification and ultrafiltration, theenzyme was stored at 6 mg/ml at 4° C. Assay plates of compound orvehicle plus buffer were set up using automated robotics to a volume of170 μl. The reaction was initiated by the addition of 20 μl of 10×substrate (A) to give a final substrate concentration of 20 μM and 10 μlof diluted enzyme to a final 0.2 nM LpPLA₂.

The reaction was followed at 405 nm and 37 ° C. for 20 minutes using aplate reader with automatic mixing. The rate of reaction was measured asthe rate of change of absorbance.

Results

The compounds described in the above Examples were tested ashereinbefore described and were found to have IC₅₀ values in the range0.0001 to 60 uM.

What is claimed is:
 1. A compounds of formula (I):

in which: Z is CR³R⁴, where R³ and R⁴ are each hydrogen or C₍₁₋₄₎alkyl,or R³ and R⁴ together with the intervening carbon atom form aC₍₃₋₆₎cycloalkyl ring; and R¹ is an aryl or heteroaryl group,substituted or substituted by 1, 2, 3 or 4 substituents selected fromthe group consisting of C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,arylC₍₁₋₁₈₎alkoxy, oxo, hydroxy, halogen, CN, COR⁵, COOR⁵, CONR⁵R⁶,NR⁵COR⁶, SO₂NR⁵R⁶, NR⁵SO₂R⁶, NR⁵R⁶, mono to perfluoro-C₍₁₋₄₎alkyl andmono to perfluoro-C₍₁₋₄₎alkoxy; X is O or S; Y is —A¹—A²—A³— in which A¹and A³ each represent a bond or a straight chain or branchedC₍₁₋₁₀₎alkylene group and A² represents a bond or O, S, SO, SO₂, CO,C═CH₂, CH═CH , C•C, CONH, NHCO, or CR⁵R⁶, providing that when A² is O,S, SO, SO₂ or CONH, A³ contains at least two carbon atoms linking the A²group and the CH₂ group in formula (I); R² is an aryl or heteroarylgroup, unsubstituted or substituted by 1, 2, 3 or 4 substituentsselected from the substituents hereinbefore defined for R¹, as well asaryl and arylC₍₁₋₄₎alkyl; W is SO₂ or a bond; and R⁷ is R¹ or ahydrocarbyl group which hydrocarbyl group may be optionally interruptedwithin the carbon chain by a group selected from the group consisting ofO, COO, OCO, CO, CONR⁸, NR⁸CO, NR⁸CONR⁹, NR⁸COO, OCONR⁸, and NR⁸, andwhich hydrocarbyl group may also be optionally substituted by 1 or 2substituents selected from the group consisting of mono toperfluoro-C₍₁₋₄₎alkyl, OR⁸, COOR⁸, CONR⁸R⁹, NR⁸COR⁹, NR⁸CONR⁹R¹⁰,NR⁸COOR⁹, OCONR⁸R⁹, NR¹¹R¹² and R¹; R⁵ and R⁶ are independently hydrogenor C₍₁₋₂₀₎alkyl; for instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl); R⁸, R⁹and R¹⁰ are independently selected from the group consisting ofhydrogen, C₍₁₋₂₀₎alkyl which may be fluorinated, including up toperfluorinated on the terminal 1 to 3 carbon atoms), C₍₁₋₂₀₎alkenyl(preferably C₍₁₂₋₁₈₎alkenyl, aryl, arylC₍₁₋₁₀₎alkyl,C₍₁₋₁₀₎alkoxyC₍₁₋₁₀₎alkyl, or aryloxyC₍₁₋₁₀₎alkyl and in which an arylgroup may have one or two substituents selected from the groupconsisting of halogen, C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎alkoxy, aryloxy andCOOC₍₁₋₂₀₎alkyl; and R¹¹ and R¹² are independently selected from one ofthe values hereinbefore defined for R⁸ and R⁹ or R¹¹ and R¹² togetherwith the nitrogen atom to which they are attached form a 5- to 7membered ring optionally containing one or two further heteroatomsselected from the group consisting of oxygen, nitrogen and sulphur, andoptionally substituted by one or two substituents which is hydroxy, oxo,C₍₁₋₄₎alkyl, phenyl, or benzyl.
 2. A compound as claimed in claim 1, inwhich Z is CH₂.
 3. A compound as claimed in claim 1 in which R¹ is anaryl group selected from the group consisting of phenyl, naphthyl, and a5- or 6- membered, monocyclic heteroaryl group containing 1 or 2nitrogen heteroatoms.
 4. A compound as claimed in claim 3 in which R¹ isselected from the group consisting of pyridyl, pyrimidyl and pyrazolyl.5. A compound as claimed in claim 1 in which X is S.
 6. A compound asclaimed in claim 1 in which A¹, A² and A³ each represent a bond or A¹and A³ are straight chain C₍₁₋₁₀₎alkylene groups and A² is CO, C═CH₂ orO.
 7. A compound as claimed in claim 1 in which R² is phenyl optionallysubstituted by 1, 2 or 3 substituents selected from the group consistingof halogen, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkoxy, phenyl and benzyl.
 8. A compoundas claimed in claim 1 in which R²YCH₂X is a 4-fluorobenzylthio group. 9.A compound according to claim 1 in which W is a bond.
 10. A compoundaccording to claim 1 in which R⁷, when a hydrocarbyl group, isC₍₁₋₂₀₎alkyl, C₍₂₋₂₀₎alkenyl, C₍₂₋₂₀₎alkynyl, C₍₃₋₆₎cycloalkyl,C₍₃₋₆₎cycloalkylC₍₁₋₅)alkyl, or C₍₁₋₁₅₎alkoxyC₍₁₋₁₀₎alkyl each of whichmay be optionally substituted by 1 or 2 substituents selected from thegroup consisting of mono to perfluoro-C₍₁₋₄₎alkyl, OR⁸, COOR⁸, CONR⁸R⁹,NR⁸COR⁹, NR⁸CONR⁹R¹⁰, NR⁸COOR⁹, OCONR⁸R⁹, NR¹¹ R¹² and R¹.
 11. Acompound according to claim 1 in which W is a bond and R⁷ is: (a)C₍₁₋₁₀₎alkyl which is substituted by one or two substituents selectedfrom the group consisting of hydroxy, C₍₁₋₁₀₎alkoxy, COOC₍₁₋₁₀₎alkyl,CONR⁸R⁹, NR⁸CONR⁹R¹⁰, NHCOR⁸ in which R⁸, R⁹ and R¹⁰ is eachindependently C₍₁₋₂₀₎alkyl), NR¹¹R¹², phenyl which may be optionallysubstituted by COOC₍₁₋₁₆₎alkyl and heteroaryl; or (b) R⁷ is a phenyl ora phenylC₍₁₋₈₎alkyl group substituted on the phenyl ring by 1 or 2substituents selected from the group consisting of C₍₆₋₁₂₎alkyl,C₍₆₋₁₂₎alkoxy, COOH, COOC₍₆₋₁₂₎alkyl and CONHC₍₆₋₁₂₎alkyl; or (c) R⁷ isheteroarylC₍₁₋₈₎alkyl in which the heteroaryl ring is monocyclic with 5to 6 members and one or two heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulphur.
 12. A compound according atclaim 1 in which W is a bond and R⁷ is a (CH₂)_(n)BR¹³ where n is aninteger from 1 to 6, B is NR¹⁴CO, CONR¹⁴, NR¹⁴CONR¹⁵, NR¹⁵COO in whichR¹⁴ and R¹⁵ are independently hydrogen or C₍₁₋₆₎alkyl; and R¹³ isC₍₈₋₁₈₎alkyl which is optionally substituted by fluorine, including upto perfluorinated on the terminal 1 to 3 carbon atoms, C₍₈₋₁₈₎alkenyl,phenyl C₍₁₋₆₎alkyl and phenylC₍₁₋₈₎alkoxyC₍₁₋₆₎alkyl in which phenyl maybe unsubstituted or substituted by halogen or C₍₁₋₆₎alkyl.
 13. Acompound of formula (I) as defined in claim 1 selected from the groupconsisting of:1-(4-hydroxycyclohexyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-yl-methyl)pyrimidin-4-one;1-(2-methoxyethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-(1-imidazolyl)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-(1-morpholino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-(2-oxo-1-pyrrolidino)prop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-(pyrimidin-5-ylmethyl)pyrimidin-4-one;1-(3-dimethylaminoprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-hydroxyprop-1-yl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one;1-(3-methoxyprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(3-phenylprop-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(5-hydroxypent-1-yl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(pyrid-2-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one;1-(pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;1-(pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(pyrid-3-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one;1-(pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;1-(pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;1-(pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thio-5-benzylpyrimidin-4-one;1-(pyrid-4-ylmethyl)-2-(8-(4-chlorophenyl)oct-1-yl)thiopyrimidin-4-one;1-(2-(pyrid-2-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(2-(pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one;1-(2-(pyrid-3-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;and1-(2-(pyrid-4-yl)ethyl)-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-((1-methyl-2-oxo-pyrid-4-yl)methyl)pyrimidin-4-one.14. A compound selected from the group consisting of:2-(4-fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one;1-methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;1-(N-(dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;and1-(N-methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one.15. A pharmaceutical composition comprising a compound of formula (I) asclaimed in claim 1 and a pharmaceutically acceptable carrier.
 16. Amethod of treating atherosclerosis which method involves treating apatient in need thereof with a therapeutically effective amount of acompound of formula (I) as claimed in claim
 1. 17. A process forpreparing a compound of formula (I)

in which: Z is a bond and R¹ is halogen; or Z is CR³R⁴, where R³ and R⁴are each hydrogen or C₍₁₋₄)alkyl, or R³ and R⁴ together with theintervening carbon atom form a C₍₃₋₆)cycloalkyl ring; and R¹ is an arylor heteroaryl group, unsubstituted or substituted by 1, 2, 3 or 4substituents selected from the group consisting of C₍₁₋₁₈₎alkyl,C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, oxo, hydroxy,halogen, CN, COR⁵, COOR⁵, CONR⁵R⁶, NR⁵COR⁶, SO₂NR⁵R⁶, NR⁵SO₂R⁶, NR⁵R⁶,mono to perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; X is Oor S; Y is —A¹—A²—A³— in which A¹ and A³ each represent a bond or astraight chain or branched C₍₁₋₁₀₎alkylene group and A² represents abond or O, S, SO, SO₂, CO, C═CH₂, CH═CH , C•C, CONH, NHCO, or CR⁵R⁶,providing that when A² is O, S, SO, SO₂or CONH, A³ contains at least twocarbon atoms linking the A² group and the CH₂ group in formula (I); R²is an aryl or heteroaryl group, unsubstituted or substituted by 1, 2, 3or 4 substituents selected from the substituents hereinbefore definedfor R¹, as well as aryl and arylC₍₁₋₄₎alkyl; W is a bond and R⁷ ishydrogen; or W is SO₂ or a bond; and R⁷ is R¹ or a hydrocarbyl groupwhich hydrocarbyl group may be optionally interrupted within the carbonchain by a group selected from the group consisting of O, COO, OCO, CO,CONR⁸, NR⁸CO, NR⁸CONR⁹, NR⁸COO, OCONR⁸, and NR⁸, and which hydrocarbylgroup may also be optionally substituted by 1 or 2 substituents selectedfrom the group consisting of mono to perfluoro-C₍₁₋₄₎alkyl, OR⁸, COOR⁸,CONR⁸R⁹, NR⁸COR⁹, NR⁸CONR⁹R¹⁰, NR⁸COOR⁹, OCONR⁸R⁹, NR¹¹R¹² and R¹; R⁵and R⁶ are independently hydrogen or C₍₁₋₂₀₎alkyl, for instanceC₍₁₋₄₎alkyl (e.g. methyl or ethyl); R⁸, R⁹ and R¹⁰ are independentlyselected from the group consisting of hydrogen, C₍₁₋₂₀₎alkyl which maybe fluorinated, including up to perfluorinated on the terminal 1 to 3carbon atoms), C₍₁₋₂₀₎alkenyl (preferably C₍₁₂₋₁₈₎alkenyl), aryl,arylC₍₁₋₁₀₎alkyl, C₍₁₋₁₀₎alkoxyC₍₁₋₁₀₎alkyl, or aryloxyC₍₁₋₁₀₎alkyl andin which an aryl group may have one or two substituents selected fromthe group consisting of halogen, C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎alkoxy, aryloxyand COOC₍₁₋₂₀₎alkyl; and R¹¹ and R¹² are independently selected from oneof the values hereinbefore defined for R⁸ and R⁹ or R¹¹ and R¹² togetherwith the nitrogen atom to which they are attached form a 5- to 7membered ring optionally containing one or two further heteroatomsselected from the group consisting of oxygen, nitrogen and sulphur, andoptionally substituted by one or two substituents which is hydroxy, oxo,C₍₁₋₄₎alkyl, phenyl, or benzyl; which process comprises: (a) treating acompound of formula (IIA):

 in which Z and R¹ are the same as in Formula (I) with a compound offormula (III): R²YCH₂L¹  (III)  in which R² and Y are the same as inFormula (I); and L¹ is a leaving group; to give a compound of formula(IA):

 in which Z, Y, R¹ and R² are the same as in formula (I) and X is S; or(b) treating a compound of formula (IV):

 in which Z and R¹ are the same as in formula (I) and L² is a leavinggroup which is halogen, alkylthio, or —NHNO₂, with a compound of formula(V): R²YCH₂XH  (V)  in which X, Y and R² are the same as in formula (I)in a solvent such as pyridine, to give a compound of formula (IA); andthereafter; treating a compound of formula (IA) form (a) or (b) abovewith a compound of formula (VI): R⁷WL¹  (VI)  in which L¹, W and R⁷ arethe same as in formula (I); to give a compound of formula (IB):

 in which X, Y, Z, R¹ and R² are the same as in formula (I), and WR⁷ isthe same as in formula (I) other than -H; (c) treating a compound offormula (IIB):

 in which W is a bond, Z and R¹ and R⁷ are are the same as defined informula (I), except the R⁷ is not H; with a compound of formula (III) ashereinbefore defined, to obtain a compound of formula (IB); and,thereafter; treating a compound of formula (IA) or (IB) in which X is Swith a compound of formula (V): R²YCH₂OH  (VII)  in which Y and R² arethe same as in formula (I); to give a corresponding compound of formula(I) in which X is O; or (d) for a compound of formula (I) in which Z isa bond and R¹ is halogen, treating a compound of formula (VIII):

 in which W, Y, R², and R⁷ are the same as in formula (I) with ahalogenating agent to form a compound of formula (I) in which Z is abond and R¹ is bromine.